1
Q
In order for cells to survive, what must they do in regards to ECF? What is the control of this ECF/ H2O/ Na+ stores in the body?
A
- Cells need to maintain ECF within well defined limits.
- Gi tract will contribute to the amount of H20 in the body as well as Na+ ect. But kidneys are the main control center of water and salt maintenance.
2
Q
What is the main control center of water and salt maintenance? What enables mammals to survive in variable conditions?
A
- kidneys are the main control center of water and salt maintenance.
- Kidneys enable mammals to survive in variable conditions.
3
Q
Where is urine modified?
A
kidneys
4
Q
What is the blood supply of the kidneys? Where does it come from?
A
Renal artery -> comes from the aorta
5
Q
What are the functions of the kidneys?
A
- Filtration of blood
- Production of urine
- reabsorption of filtered substances adjusting salt and water excretion to maintain constant ECF volume and osmolality.
- Excretion of met wastes and xenobiotics
- Water/ acid-base
- production of glucose (gluconeogenesis)
- endocrine fxn
6
Q
Will dialysis allow for all kidney functions to occur?
A
No, only allows for:
• Filtration of blood
• Production of urine
• reabsorption of filtered substances adjusting salt and water excretion to maintain constant ECF volume and osmolality.
7
Q
What are some signs of kidney dysfunction in a 13 year old cat ?
A
- PU/PD, Vomiting (accumulation of urea/ substances that would be excreted by kidneys)
- Clinical exam: pale mm, both kidneys feel small upon palpation (decrease size with chronic disease) . Hematocrit 21% (decrease erythropoietin) , Creatinine 7.5.
- animal cannot concentrate urine
8
Q
What is calcitriol?
A
Stimulated by PTH in response to hypocalcemia.
9
Q
What is Renin?
A
Hormone activator, renal regulation of blood pressure, essential part of renin angiotensin aldosterone system (RAAS)
10
Q
What is erythropoietin?
A
Hormone (glycoprotein, growth factor) essential for erythropoiesis.
11
Q
How is calcitriol synthesized?
A
From food or the conversion of UV rays ( 7-dehydocholesterol. This is then converted to Vitamin D3 -> which is then converted by 25-hydroxylase in liver to 25(OH)-Vitamin D3 -> then 1-hydroxylase in kidney will convert 25(OH)-Vitamin D3 to 1,25(OH)20Vitamin D3 (Calcitriol)
12
Q
What is a protein involved in calcium absorption that is synthesized from vitamin D?How is it synthesized/ how is calcium brought into cell and removed from cell?
A
• Calbindin is one of the proteins synthesized by Vitamin D
Vitamin D binds to receptor which then will go to nucleus. mRNA will leave nucleus to synthesize protein (i.e Calbindin). Calbindin will take the calcium from apical membrane and transfer it to basolateral membrane. We have calcium channels at the membrane. Stimulation of ATPase will pump calcium out into the blood.
13
Q
What triggers renin?
A
• Renin is triggered by acute drop in plasma volume and blood pressure.
14
Q
What does renin do?
A
• Renin is a hormone that will activate the angiotensinogen and will shorten (removing the last 4 AA) which will give you an angiotensin I.
◦ A converting enzyme (mainly found in lung) will then cut last 2 AA off, and will give you Angiotensin II. Angiotensin II has 8 AA.
15
Q
What is erythropoietin? What can trigger it aside from low RBC?
A
- Erythropoietin is essential for new RBC formation.
- Can be triggered by high altitude.
16
Q
How does erythropoietin influence RBC formation?what occurs if this synthesis does not
A
- Erythropoietin will go to the bone marrow and will find committed erythroid precursors which will mature and will end up making mature erythrocytes at the end.
- If that doesn’t work patients will develop anemia.
17
Q
What are the main parts of the Kidney? What is the functional unit of the kidney?
A
Cortex and Medulla. functional unit is nephron
18
Q
What can be found in the cortex? In the Medulla?
A
- Black line is approximate border of cortex and medulla. In the cortex you will find afferent and efferent arterioles, glomerular capillaries, peritubular capillaries, collecting ducts, ect Straight part of henlees loop is in the cortex, Straight ascending has partial in medulla and partial in the cortex.
- In medulla you will find peritubular capillaries collecting ducts. Thin segments of henlees loop are found in the medulla.
19
Q
How many nephrons care found in the canine kidney? Feline? Cow?
A
Dogs: 400,000
Cats: 190,000
Cows: 4 million
20
Q
Can nephrons be replaced?
A
no, only partially regenerated.
21
Q
What are the 2 types of nephrons? Where are they found?
A
◦ Cortical nephrons: cortex, short loops of henlee, and are supplied by peritubular capillaries.
◦ Juxtamedullary nephrons: located near cortex/medulla junction, efferent arterioles give rise to long straight capillaries (vasa recta) that descend into renal medulla. Extremely long loops of henlee ( critical for urine concentration)
22
Q
What are malphigahian bodies? what is it consisted of?
A
• Malpighian bodies: located in renal cortex, consists of glomerulus (capillaries) surrounded by bowmans capsule (double walled capsule)
23
Q
What are the proximal tubules?
A
• Proximal tubule: longest part of nephron, consisting of a proximal and convoluted tubule and straight part
24
Q
What is the loop of henlee?
A
• Loop of henlee: consists of thick descending limb ( extending into renal medulla), thin descending limb, thin ascending limb (only nephrons which have long loops( juxtamedullary nephrons)) and thick ascending limb (TAL, macula densa)
25
What are the distal tubules and collecting ducts?
* Distal tubule: straight and convoluted part (DCT)
* Collecting ducts: Extend through renal cortex and medulla
26
Where does the collecting ducts open in the renal pelvis?
Renal Papilla
27
What percentage of cardiac output goes to the kidneys?
20-25%
28
What is the path of renal blood flow?
• Abd aorta -\> Renal artery -\> Interlobar arteries -\> arcuate artery -\> interlobular arteries ( to the renal capsule) -\> afferent arterioles -\> glomerular capillaries -\> efferent arterioles -\> Peritubular capillaries/ vasa recta (no vasa recta in cortical nephrons)
29
What happens if O2 and energy supply are interupted in the kidneys? What is O2 used for? ATP?
◦ Active Transport Occurs in the proximal tubules, ATP is used
◦ Oxygen is needed for ETC ( aerobic metabolism)
◦ What happens if O2 and energy supply are interrupted?
‣ Infarction -\> tissue damage. This will cause ischemia.
30
What is the consequences of renal ischemia?
* Renal ischemia causes severe histological and functional damage to the kidney.
* Interruption of o2 to tissue, and this will cause inflammatory response and increased levels of ROS. ROS are highly reactive that damage DNA, lipids and protein's.
* Inflammatory cells infiltrate the injured tubular cells, damaged cells activate apoptotic pathways. Renal fxn becomes severely impaired.
31
What cells can be regenerated in the kidneys? What occurs to these cells during ischemia? What occurs after cells no longer are receiving ischemic injury?
* Tubular cells can be regenerated.
* During ischemia -\> there is a loss of the brush border and carriers from basolateral membrane can be seen at the apical membrane. this is clear in staining. This causes a loss in polarity.
* Some cells will go through apoptosis, some will regenerate. Luminal obstruction will occur, but then will improve with time. ( is this AKI)
32
What occurs to cells during ischemia repair, and what is this dependent on?
* Some cells will be injured and loose brush border. Their will be migration and proliferation to replace and regenerate these cells.
* This depends on severity of damage and duration of ischemic injury.
33
What is the path of filtration of urine? How much urine is filtrated through this area? How much is excreted? What manages this?
* Filtration through glomerular capillaries into Bowmans capsule (180 L per day)
* about 1 L is actually excreted and the rest is resorbed. This is why the nephrons are so important.
* Glomerulus compact network of capillaries that retains cellular components and proteins.
34
Where is filtrate accumulated?
Bowmans space
35
What is Glomerular filtrate?
• Glomerulus produces fluid that is almost identical to plasma -\> glomerular filtrate.
36
What determines the rate of glomerular filtration? What percentage of blood plasma flowing through kidney is filtered through glomeruli?
* Rate of glomerular filtration is dependent on the rate kidney is perfused by blood. -\> called renal blood (plasma) flow.
* 20% of blood plasma flowing through kidney is filtered through glomeruli.
37
In this image, what is REAB, GFR, Black arrow, and Urinary excretion refering to ?
* Black arrow indicates where Drug metabolites and xenobiotics are eliminated.
* GFR is where filtration occurs -\> creation of primary urine
* REAB is where reabsorption of valuable substances I.e glucose, amino acids, ect.
- Urinary excretion is where urinary excretion occurs.
38
What is found with by finding the difference between GFR and REAB? What % of GFR is excreted as urine? What occurs with the rest?
* Difference between GFR and REAB = Urinary excretion
* Less than 1% GFR is excreted as urine. more than 99% is resorbed.
39
What is glucosuria? Why does it occur?
• Glucosuria -\> limit of reabsorption of glucose, so excess will end up in urine. Glucose carrier can only transport so much.
40
What are the components that make up the structure of the glomerulus?
* Alot of capillaries.
* Podocytes are wrapping capillaries, and are encased within bowmans capsule.
* Bowmans capsule lined with parietal epithelium.
Bowmans space is where filtrates collect.
41
What are the components of the filtration barrier?
* Capillary endothelial cells (fenestrated )
* Glomerular basement membrane, (no cells but many glycoproteins).
* Visceral epithelium-\> podocytes
42
What is each layer of the glomerular basement membrane in this picture?
How can you tell what each layer is?
A.) Lamina rara interna
B.) Lamina Densa ( contains glycoproteins)
C.) Lamina Rara externa
You can tell by their density and location.
43
What can be found in the lamina densa? What does this cause in the glomerular capillaries?
Lamina densa is especially ritch in glycoproteins like laminins, type IV collagens, proteoglycans, ect.
The glomerular capillaries are, therefore relatively impermeable to proteins. The glomerular filtrate is essentially proten free.
44
What determines filterability? What substances have 100% filterability? Which do not ? What is the substance with the lowest filterability?
• Filterability is based on molecular weight and size. Water, sodium, and glucose all have 100% filterability. Myoglobin, hemoglobin, and albumin all do not have 100% and their percentages are 75%, 3%, and less than 1% respectively.
Albumin is bigger than hemaglobin, and almost completely, unable to be filtered.
• Electrolytes such as sodium and small organic compounds ( i.e glucose) are filtered freely as water.
45
What molecular properties does filterability rely on?
• Size -\> filterability of solutes is inversely related to size -\> bigger = harder to filter.
## Footnote
* Electrical charge -\> negatively charged molecules are filtered less easily than positively charged molecules of the same molecular size
* Cationic substances are more filtered than anionic
• Plasma protein binding: this can be seen as protective mechanism for some solutes such as calcium. Some drugs will be retained in circulation for defined time period before being eliminated.
◦ All solutes bound to albumin will remain in the blood. Free solutes will be excreted.
46
What is the main driving forces for filtration? What are the forces opposing filtration?What is the oncotic pressure in bowmans space?
• Main driving forces for filtration is glomerular capillary hydrostatic pressure.
* The forces opposing filtration are the hydrostatic pressure in bowmans space and the oncotic pressure of the blood plasma.
* Essentially zero oncotic pressure in bowmans space.
47
What will occur to net filtration as we move across the glomeruli? Protein osmotic pressure ? Where is the start of glomeruli and where is considered the end?
* Protein osmotic pressure will increase as we move across glomeruli.
* Net filtration pressure will decrease as we move across the glomeruli. This occurs when the hydrostatic pressure is nearly constant
• Start is afferent arteriole, end is efferent arteriole.
48
Why is GFR important? What is the total volume of fluid filtered by the glomeruli into bowmans space per minute per kg?
GFR is important to analyze renal function.
total volume of fluid filtered by the glomeruli into bowmans space per minute per kg ~ 3.7 ml/min/kg
49
What can GFR be calculated with? What are the properties of substances?
- GFR can be calculated using indicator substances.
Properties of Substances:
- Must be freely filterable
- Their filtered amount must not change due to reabsorption or secretion in the tubule.
- They must not be metabolized in the kidney
- They must not alter renal function
50
What are some candidates for GFR calculation?
Inulin, and Creatine
51
How do we find GFR via inulin concentration?
GFR = Urine excretion rate \* inulin (concentration) in urine/ inulin (concentration) in plasma.
52
Why is inulin less used in calculations for GFR?
Because measurement of creatinine clearance does not require intravenous infusion into the patient, this method is much more widely used than inulin clearance for estimating GFR clinically .
53
What is creatinine? What is it used for? What does an increase in plasma creatinine indicate?
* Creatinine is a by product of muscle metabolism. In dogs it is not secreted by tubular system. In some other species up to 10% is secreted)
* In clinical practice, serum creatinine level is also useful to assess renal function.
* If creatinine in plasma is elevated -\> GFR is reduced
54
How do you calculate BSA (Body Surface Area)?
55
How do you calculate GFR when using creatinine?
GFR = Volume urine \* urine creatinine / plasma creatinine
Divide answer by BCS to get ml/min/m2
-\> unit: ml/min or ml/min/m2
56
What is the calculation for RPF?
GFR = Volume urine \* urine PAH/ plasma PAH -\> unit ml/min
- Divide answer by body surface area to get ml/min/m2
57
What is the calculation for RBF?
RBF = RPF / (1-hct) -\> ml/min
Divide answer by Body surface area to get ml/min/m2
58
How is fractional filtration calculated?
FF = (GFR/RPf )x 100 -\> %
You can use the GFR and RPF that has been divided by BSA to calculate the answer without having to divide it by BSA.
59
What is GFR measured by?
GFR is measured by the clearance of a free filterable substance that is neither reabsorbed nor secreted by the renal tubules (= inulin or creatinine)
60
What is the Renal Plasma blood flow?
Renal plasma flow (RPF, the volume of plasma delivered to the kidneys) is measured uring PAH (= para-aminohippuric acid) which is filtered and (in contrast to creatinine/inulin) additionally secreted by the renal tubules. The formula is exactly the same as for GFR but with PAH concentration instead of creatinine concentration
61
What is Renal Blood Flow?
Renal blood flow, RBF, the amount of blood delivered to the kidneys, is calculated from the measured RPF and the hematocrit
62
What is the Filtration Fraction, or fractional filtration?
Filtration fraction or fractional filtration, FF, the fraction of the renal plasma flow that is filtered across the glomerular capillaries, is calculated dividing GFR by RPF
63
How is GFR kept within the physiologic range? What can cause changes to the pressure of glomerular capillaries and peritubular capillaries?
• GFR is kept within physio range by renal modulation of systemic blood pressure and intravascular volume, as well as intrinsic control of renal blood flow.
64
What is the window which autoregulatory effects cqan normalize the GFR and R?BD?
* Autoregulatory window btwn 80-180 mmHg : short term changes in systemic blood within this range will only minimally alter GFR and RBF
* Variation above will cause issues with urine production, ect.
65
What are the responses that regulate blood flow?
1. ) Myogenic reflex ( Bayliss effect)
2. ) Tubulo glomerular feedback
3. ) Renin Angiotensin Aldosterone System
66
What is the Myogenic reflex set off by? What is its mechanism of action?
The Myogenic reflex detects changes in glomerular perfusion. This occurs as a local effect because of increased tension of arteriolar wall, which causes depolarization of vascular smooth muscle cells. Calcium will then enter the cell and cause contraction of muscle cell and constriction of afferent arteriole. When arteriole blood pressure falls a dialation of the affterent arteriole occurs
Like closing water supply when too much water is coming out.
67
What is the mechanism of the tubuloglomerular feedback?
This detects changes in tubule fluid delivery. Part of tubule in close contact with glomerulus and this detects changes in tubule fluid delivery.
• Renin is synthesized in cells located in the wall of the afferent arteriole (juxtaglomerular cells) and used locally. They are in close contact with macuala densa.
• High concentration of NaCl in macula densa will lead to depolarization of cells and release of ATP basolaterally. This will then lead to suppression of renin release from JGC. Messangial cells will contract, and there will be increased resistance of afferent arteriole. Reduced GFR is the overall consequence.
68
What is the job of TGF? How does the nephron adjust the GFR? Where is sodium and chloride reabsorbed?
* TGF mechanism prevents a flow rate that would exceed the transport capacity of the tubular system.
* The nephron will adjust the GFR to the reabsorption capacity of solutes. Macula densa is where sodium and chloride are reabsorbed.
69
If an increase in sodium or chloride is sensed what will occur?
If an increase in sodium or chloride is sensed, it indicates an increased GFR so the response is to close the afferent arteriole so that they don't loose as much Na and Cl
• RAAS -\> systemic response.
70
What causes the kidneys to release renine? What is the pathway of Renin to angiotensin II?
• Kidney releases renin in response to decrease in arterial pressure. Renin will convert angiotensinogen ( which comes from liver) to angiotensin I in plasma. Angiotensin I will be converted ( by ACE) to angiotensin II in the capillaries of the lungs. Angiotensin II has many effects in the body.
71
What are the effects of Angiotensin II on the body?
◦ Increased thirst( which leads to increased fluid intake) , increased ADH (which leads to increased renal absorption of H2O), increased arteriolar contraction (which leads to increased TPR), increased aldosterone ( which leads to increased renal absorption of Na+)
◦ In peritubular capillaries : decreased hydrostatic pressure, increased protein osmotic pressure. ( which leads to increased renal reabsorption of H2O and salt)
◦ All of these changes drive arterial blood pressure towards normal
72
What are the vasodilatory agents?
* NO - Produced by Nitric Oxide Synthase
* PGE2- Produced by Coxygenase (COX-2)
73
What is the role of NO and PGE2?
◦ These both modulate messangial cell constriction to prevent an excessive reduction in single nephron GFR (fxn as break)
74
What can occur with prolonged use od NSAIDS?
◦ Prolonged use of NSAIDs can lead to renal failure. (Related to blockage of COX-2 (which is responsible for the creation of many important prostaglandins)
75
What are the constricting factors?
* Constricting factors: Endothelin, TXA2, ANG2
* a- adrenergic stimulation
76
Critical thinking: What happens to the GFR if ...
↑ RBF →
↑ Systemic pressure →
↑ afferent arteriole tone →
↑ efferent arteriole tone (slight) →
↑ ↑ efferent arteriole tone (strong) →
↑ hydrostatic pressure of Bowman‘s capsule (PBC) →
↑ RBF → ↑ GFR
↑ Systemic pressure → ↑ GFR
↑ afferent arteriole tone → ↓ GFR
↑ efferent arteriole tone (slight) → ↑ GFR
↑ ↑ efferent arteriole tone (strong) → ↓ GFR
↑ hydrostatic pressure of Bowman‘s capsule (PBC) → ↓ GFR
77
What is primary urine?
• primary urine, filtrate that accumulates in the capsular space between glomerulus and bowmans capsule. Same concentration of NaCl and glucose as plasma.
78
What is tubule fluid?
• Tubular fluid ( primary urine inside tubular system) passes through tubular system and is continuously modified by tubular reabsorption. This will become final urine at the end.
79
What is the fractional excretion rate? What is the calculation for it?
• Fractional excretion rate: net rate of reabsorption and secretion of a filtered substance and indicator of fxn integrity of renal tubules.
• FEx = (Urine concentration of X /Plasma concentration of x) / (Ucreat/ Pcreat) \* 100
◦ this will give you percentage of filtered x that is excreted
80
What is the function of the glomerulus?
Glomerulus: Filters the blood (Solutes, water, Urea, Creatinine) = primary urine
81
What is the function of the proximal tubule?
Proximal Tubule: Reabsorbs most filtered solutes eg. glucose, amino acids, peptides, proteins, Na+, K+, Cl-, HCO3- Ca ++, Mg++ Reabsorbs water Excretion of waste and xenobiotics
82
What is the function of the thin limbs of henlees loop?
Maintain medullary hypertonicity, reabsorbs water, Na+, Cl-
83
What is the function of the thick ascending limb?
Reabsorbs Na+, K+, Cl- Dilutes tubule fluid and maintain medullary hypertonicity
84
What is the function of the distal convoluted tubules?
Reabsorbs Na+, Cl-, Ca ++, Mg++ Conecting segments regulate acid, HCO-, ammonia, Ca ++, Na+, K+, and water excretion
85
What is the function of the collecting ducts?
Collecting ducts: Regulates acid, HCO-, ammonia, Na+, K+, and water excretion/reabsorption = final urine
86
What are the components of the proximal tubule?
PT cells are polarized (apical and
basolateral membrane)
* Brush borders (microvilli)
* Tight junctions
87
What structures are present on the apical membrane of proximal tubule cells? The basolateral membrane? What is found below the basement membrane?
Apical membrane has brush borders (on picture, BB)
Basolateral membrane has infoldings (micropedici ‚tiny feet‘)
Don‘t forget the peritubular capillaries below the basement membrane
88
What are the mechanisms that move tubule fluid back into the blood?
Transcellular pathway
and
Paracellular pathway
89
What is the transcellular pathway?
Transcellular pathway: largely by carrier-mediated transport substances cross
the apical membrane, cytoplasm, and basolateral plasma membrane into the
interstitial fluid
From interstitial fluid -\> to the peritubular capillaries
90
What is the paracellular pathway?
Paracellular pathway: tubule fluids pass through the epithelium accross the tight junctions (passive difussion or solvent drag). Substances enter the lateral
intercellular space and the interstitial fluid
From interstitial fluid -\> peritubular capillaries
91
What are the transport mehanisms in the proximal tubules ? What is each driven/ fueled by?
1. Primary active transport: Fueled directly by ATP consumption, e.g., Na+, K+- ATPase (located basolaterally)
2. Secondary active transport: Driven by the electrochemical gradient produced by the primary active transporter, e.g., SGLT
3. Tertiary active transport: The carrier is driven by the gradient generated by a
secondary active transporter, e.g., peptide, H+ cotransporter
92
Why is urinalysis ideal to run in a clinic setting for patients with potential kidney issues?
Urine analysis is a simple and cheap test that provides you with valuable information
93
Before begining any microscopic analysis what should you do?
A physical examination
A macroscopic analysis using fresh urine (within 30 min after collection). Use your senses and observe for clarity/turbidity, color, etc
You may use urine stripes
Refractometer to analyze specific gravity
Microscopic analysis (look for sediments)
You may use some special reagents for protein analysis
94
How do Specific Gravity and Osmolality differ? Do they correlate?
SG and osmolality correlate as well but remember SG of the urine varies depending on the type of solute present whereas osmolality depends on the amount of osmotically active particles regardless of their size
95
How can you calculate osmolality from specific gravity?
Osmolality of the urine can be calculated in dogs using the SG (the last two digits of SG multiplied by 36 approx) For plasma osmolality use glucose, Na and BUN concentration as follows:
Plasma osmolality = 2 [Na] + Glucose/18 + BUN/2.8 Na = mmol/L; Glucose and BUN = mg/dL
96
What is included in the combur test (Roche/ urine dipsticks)?
- Leukocytes
- Nitrates
- pH
- Protein level
- Glucose level
- Ketone level
- Approximate Specific Gravity
- Urobilinogen
- Blood presence
- Hemaglobin
97
Will specific gravity change with proteinuria? Osmolality?
SG will change with proteinuria , Osmolality will not.
98
What is pH dependent on? What would you see in a cow? What would you see in a dog or cat?
• pH is dependent on the diet ( Cows you will see more alkaline pH, while carnivores will have more acidic pH)
99
What is specific gravity used to determine? What instrument would you read it on?
Used for renal concentration ability.
You would use a refractometer to measure specific gravity.
The amount of refraction is proportional to the amount of solutes in that liquid
100
Boston Terrier, female, 11-y old Increased water consumption in the last month Large urine volumes.
Clinical examination: The dog shows no major abnormalities and is alert - Hematocrit is 43% (range 35-55%)
- Serum creatinine is 0.5 mg/dL (normal 0.5-1.8 mg/dL)
- Glucose (urine strip) is 4+
- Glucose in plasma is 255 mg/dl (normal, 80 – 120 mg/dl)
Why is it likely this dog has glucose in its urine? What may this indicate clinically?
• Amount of glucose is higher than what carriers can take in via reabsorption. So this is likely Diabetic patient since there is an increase of glucose excreted in the urine and elevated glucose plasma concentration.
101
At the basolateral membrane of proximal tubule cells, how else can substances be transported into the interstitium?
At the basolateral membrane some substances are transported by passive transport into the interstitium
102
How does tertiary active transport work in regards to resorption of peptides?
* H+ gradient enables the transport of di and tri-peptides by the Proximal tubules by tertiary active transport
* Oligopeptides will undergo hydrolysis by extracellular peptidases and will be reabsorbed as free amino acids.
103
How is bicarbonate reabsorption and acid secretion occuring in the proximal tubules?
* Bicarb reabsorption and acid secretion in the PT ( also Na+ driven)
* Bicarb reabsorbed in PT as CO2
* There are 2 carbonic anhydrase's in the kidneys, one membrane associated, the other located in the cytosol of PT cells.
* The chemical sodium gradient drives the Na/H+ antiporter ( Na/H exchanger, NHE3)
104
How is chloride ion reabsorption occuring in the proximal tubules? K+? Ca++?
* Cl - ions reabsorption occurs paracellular and transcellular driven by chemical (H2O movement) and electrical gradients
* Ca++ uptake paracellular via solvent drag
* K\_ reabsorption mainly paracellular.
105
What is the category of the substances secreted by the proximal tubules? What will cause them to be poorly filtered by the glomerulus?
Organic ions -\> endogenous waste products -\> exogenous drugs, toxins
If these organic ions are protein bound in the plasma, they will be poorly filtered by the glomerulus
106
What are some of the mechanisms the body uses to sort out harmful substances?
The body can usually sort out harmful substances by different mechanisms (taste sense, digestive enzymes, hepatic and renal excretion)
107
What mechanism does proximal tubules utilize to secrete waste products and xenobiotics?
Active transport Mechanisms
108
What are organic anions secreted?
- PAH
- Oxalate
- Drugs such as penicillin, analgetics, diuretics, etc
- Herbicides such as paraquat
- Several conjugated substances (glucuronic acid)
109
What carriers mediate the secretion of organic anions in the proximal tubules?
OATs (Organic Anion Transporters)
MRP-2 (Multidrug Resistance Protein 2)
110
What organic cations are secreted by proximal tubule cells?
Organic cations (OC+) secreted include:
- Epinephrine
- Choline
- Histamine, Serotonine
- Drugs such as atropin, morphin, etc
111
What transporters mediate organic cations in the proximal tubules?
OCT (Organic Cations Transporters)
MDR1 (Multidrug Resistance 1)
112
What is the relevance of secretion of organic anions and cations?
Tubular secretion of endogenous organic ions, drugs, and toxins has several diagnostic and therapeutic applications. It allows for:
* Urine testing of hormones which can be an indicator of blood levels
* Urinary secretion of antibiotics helps you to identify the doses needed to reach high concentrations in the urinary tract
113
How are low molecular weight proteins reabsorbed in the proximal tubules? What is needed to have this occur?
Low-molecular-weight proteins (filtered insulin, glucagon, PTH, etc) are reabsorbed by a completely different mechanism, called „receptor-mediated endocytosis“
This process needs the presence of receptors in the plasma membrane of PT cells (megalin and cubilin)
After endocytosis ther is fusion with lysosomes and degradation of proteins into amino acids
114
Is resorption of protein in the proximal tubule saturabale? What occurs when the mechanism is over saturated?
Recall: As with many receptor-mediated processes this kind of reabsorption is saturable:
- An elevated plasma concentration of filterable proteins or an increased filtration of proteins (damage of the glomerular filter) will lead to the presence of protein in the urine, a pathologic condition called proteinuria
115
What are the 3 classifications of proteinuria?
1. Pre-renal: if the concentration of free-filterable proteins (e.g. Hb, myoglobin) in the blood is increased
2. Intrarenal: if the glomerular filter is damaged or if any process that occurs inside the kidney is impaired
3. Post-renal: loss of proteins from urine coducting system (ureters, urinary bladder, uretra) due to inflammatory processes or bacterial infections
116
What allows for the reabsorption of glucose? What is the difference between the two glucose transporters?
Reabsorption of glucose is achieved by sodium-dependent transporter (Sodium- glucose transporter, SGLT)
There are two different sodium-dependent glucose transporters: -A low-affinity one located in the pars convoluta (SGLT2) -And a high-affinity one in the pars recta (SGLT1)
Saturation can occur! (Michaelis-Menten kinetics)
117
What occurs when carriers are saturated? What will the result be with the urine? At what plasma glucose level will you see glucosuria development?
Saturation of carriers -\> less reabsorption -\> excretion in urine
Urine will contain glucose.
Glucose will cause increase in osmolality and there will be excessive water loss into the urine with resultant dehydration, a process called osmotic diuresis.
If the plasma [glucose] \> 10-15 mmol/L (normal is 5 mmol/L in humans), glucosuria develops (the presence of glucose in the urine)
118
What is a solute? Solution? Osmolarity? Osmolality?
Solute: The minor component of a solution which is regarded as having been dissolved by the solvent
Solution: A liquid or solid phase containing more than one substance, when for convenience one (or more) substance, which is called the solvent, is treated differently from the other substances, which are called solutes
Osmolarity: concentration of all osmotically active particles in a solution expressed as osmoles per liter of solution (Osm/L)
Osmolality: because volume is temperature-dependent, osmolality is more suitable in living organisms (Osm/Kg water)
119
What is the loop of henle? What is the structure/ components of the thin segments?
Abrupt change in the structure of the tubule epithelium at the end of PT
- The ‚thin segments‘ have thin epithelial membranes, no brush borders, few mitochondria, low metabolic activity
120
What are the segments that make up the loop of Henle?
1. Thick descending limb (some authors don‘t consider the
existence of this part and just call it „straight part of PT“)
2. Thin descending limb
3. Thin ascending limb
4. Thick ascending limb, also known as medullary thick ascending
limb (mTAL)
121
Repeated: What are the two types of nephrons? Which is important for urine concentration?
- Juxtamedullary nephrons- long loops of Henle that extend into the inner medulla. Especially important for urine concentration.
- Cortical nephrons short loops, no thin ascending limbs, and extend only into the outer medulla
122
What is found in the apical membrane of the thin descending limb of henles loop? What is its function? What is the consequences of these structures?
The thin descending limb of Henle‘s loop:
• highly permeable to water. Aquaporins (AQP-1) in the apical membrane
reabsorb water and send it into the medulla
• reduced permeability to sodium, chloride, and urea
123
What is the implication of reduction of permeability of sodium, chloride and urea in the thin descending loop of henle?
If water is being reabsorbed and NaCl remains in the tubular lumen ... =\> the tubular fluid becomes more concentrated (↑ osmolality) The thin descending limb helps concentrating the tubule fluid
124
What is the function of the ascending limbs of henles loop? What can be found in the medullary thick ascending limb, and what is the benefit of it?
Both, the thin and the thick ascending limbs are virtualy impermeable to water
• The thin ascending limb has a low reabsorptive capacity
• The medullary thick ascending limb (mTAL) has thick epithelial cells, high
metabolic activity and reabsorbs high amounts of sodium, chloride, potassium,
and considerable amounts of calcium, bicarbonate, magnesium
125
What is the implication of the thin and thick ascending limbs being virtually impermiable to water? What occurs in the mTAL as a result? What is another name for mTAL?
If NaCl is being reabsorbed and water cannot follow ...
=\> the tubular fluid in the mTAL becomes very diluted (↓ osmolality) and the renal medulla becomes more concentrated (↑ osmolality)
mTAL helps diluting the tubule fluid and maintaining medullary hypertonicity and is also called „diluting segment“
126
What occurs in the descending thin limb of the loop of henle?
* Water is reabsorbed
* Low permeability to solutes (NaCl and urea)
* Osmolality of the tubular fluid gradually increases
127
Where is ascending thin limb present?
Only in long loop nephrons!
* Essentially impermeable to water
* NaCl is reabsorbed
128
What is important characteristics of mTAL?
* Virtually impermeable to water
* NaCl reabsorption
* Dilution of the tubular fluid
129
What are the relevant transport systems of mTAL?
Na, K, Cl Cotransporter (NKCC), Cl- channels, K+ channels (ROMK)
Paracellular: Ca++, Mg++, Na+ (the positive charge of the lumen relative to the interstitium forces cations to diffuse from the lumen to the interstitium)
130
What mTAL relevant transport system is inhibited by furosemide?
NKCC is inhibited by furosemide, a commonly used diuretic
131
What is reabsorbed at the Distal convoluted tubules?
- Na+, K+, Cl -, Ca++, and Mg++
132
What are the relevant transport systems of the DCT?
Ca++ channels, Na+/Cl- co transporter (NCC), Cl- and K+ channels, Ca++ /Na+ exchanger
133
What can inhibit NCC?
Thiazide diuretics
134
What can be removed with thiazide diuretics?
- H2O, and Na+
135
Where is water reabsorption occuring in the kidneys? How? What can cause it?
Water reabsorption occurs in the late distal tubules, and is aquaporin mediated and can be caused by high levels of ADH
136
What is reabsorbed in the inner medullary collecting ducts? What is this important for?
Urea reabsorption via specific urea transporters. Important for urea recycling
137
What are the main cell types of the collecting duct?
Principal cells
Intercalated cells
138
What are important features of principal cells?
- Short, small projections over apical membrane
- Center cilium
- Few intracytoplasnuc vesicles and mitochondria, but many basolateral plasma membrane infoldings ( NaCl resorption through apical epithelial Na channels (ENaC
139
What are important features of intercalated cells?
- many complex membrane folds ( microplicae) over the apical surface.
- Intracytoplasmic vesicles and mitochondria
- Subdivided in type A and B
- Important for maintainting acid base homeostasis.
140
What are the collecting ducts principal cells relevent transport systems? What do they reabsorb/ secrete? What is the function of these transport custems.
NaCl reabsorption by ENaC and K+ secretion by ROML ( they can also reabsorb K+ but this is dependent on sodium reabsorption)
141
What is the function of type A intercalated cells?
Type A- Secretes H+ and reabsorbs HCO3-
142
What is the function of type B intercalated cells?
Type B - Reabsorbs H+ and Secretes HCO3-
143
What do the collecting ducts transverse the cortex and medulla and end in?
One of many papillary tips
144
Where is magnesium absorbed in the kidneys?
• Mg is absorbed in the henlees loop (thick ascending limb)
145
Where are solutes other than Mg absorbed the most in the kidneys?
Proximal convoluted tubules
146
What is the function of sodium?
* Main cation in ECF
* Maintenance of osmotic pressure and water content in ECF
* Resting membrane potential
* membrane depolarization in nerve cells
* Driving force for reabsorption of several solutes in kidneys
147
What hormones/ substances are involved in regulation of sodium reabsorption in the kidneys (Stimulation)?
Angiotensin II: Increases Na+ reabsorption in PT. Also has effects in collecting ducts due to ENaC.
Aldosterone: Stimulates Na+ reabsorption in CD
- Hyperkalemia also stimulates aldosterone release (increases apical K+ permeability through channels)
ADH stimulates -\> NKCC in TAL
148
What hormones/ substances are involved in regulation of sodium reabsorption in the kidneys (inhibition)?
NO - Regulation of systemic extracellular fluid and blood pressure: increases Na+ excretion through inhibition of Transporters ( NHE3, Na-K+ATPase, NKCC, and ENaC)
Endothelin-1: Increases Na+ excretion through inhibition of Na-K+ ATPase, NHE3, NKCC, ENaC
ANP: Inhibits aldosterone and renin release and increases Na+ excretion.
149
Where is Na+ primarily reabsorbed?
Proximal convoluted tubules (apical: antiport, various symporters; basolateral Na+ K+ ATPase, HCO3 symporter)
150
What is the function of calcium homeostaisis?
- Skeletal strength and hardness
- Release of neurotransmitters
- Blood Coagulation
- Muscle contraction
- Second messenger
151
When is PTH increased ? When is calcitonin increased?
* PTH increased when plasma calcium levels are low below 0.8.
* Calcitonin increased when plasma levels are high (above 1)
152
What does increased secretion of PTH do to in terms of calcium?
pth causes:
• mobilization of Ca+ from bone tissue
• reduced loss of ca in urine
• Forms calcitriol in kidney
153
How does vitamin D hormone affect calcium in the intestines?
Vitamin D stimulates calcium reabsorption -\> binding ca to binding prodtein (calbindin) -\> which stimulates calcium reabsorotion by calcium channels in the intestines.
154
Where is the majority of Ca++ resorbed in the kidneys? How? Where is the remaining absorbed? How?
65% of Ca++ is reasorbed in Positive Tubules (paracellular and passive), 20% in TAL ( paracellular and passive, little through the Ca++ ATPase), 10% in distal convoluted tubules ( via Ca++ channel, TRPV)
155
What stimulates ENaC?
Aldosterone
156
What does PTH do to calcium in times of hypocalcemia?
PTH increase stimulates apical uptake of ca++ through ca++ channels in TAL and DCT.
157
What are the functions of phosphorus/ phosphate?
- Most phosphorus in body is combined to O2 ( phosphate anion)
- Second major component of bones
- Components of phopholipids, proteins, nucleic acids.
- Energy transferring molecules (ATP)
- Buffer ( hydrogen phosphate and hydrogen diphosphate)
158
What hormones are involved in phosphate homeostais?
PTH and Calcitriol
159
How does PTH affect Phosphate homeostasis?
* PTH acts to increase phosphate mobilization from the bone.
* PTH increases absorption of phosphate of intestinal epithelium and the kidney.
* PTH increases excretion of phosphate from the kidney
160
What does PTH do in the proximal tubules and how does it effect phosphate levels?
PTH inhibits apical NaPi transporters in PT and increases renal excretion of phosphorus.
161
If an animal is hypocalcemic, there is a strong chance they will become \_\_\_\_\_\_\_\_\_\_
hypophosphatemic
162
What is important to remember about calcium, if it is in soluable form?
It will move with water
163
Where is phosphate reabsorption the highest in the kidneys? How? Where else?
Phosphate is reabsorbed highest in the proximal convoluted tubules via Na+ PO4- symport carrier
Next it is found (next highest) in the Distal convoluted tubules and collecting duct, its mechanism is not fully understood.
Lastly It can be reabsorbed in the loop of henlee via active and transcellular transport.
164
Where is calcium reabsorbed the most in the kidneys? How? Where else?
Ca++ is reabsorbed the most in the proximal convoluted tubules (this occurs via paracellular and solvent drag transport)
It is also reabsorbed in the loop of henlee (next area with largest reabsorption of calcium), and occurs via paracellular transport
Lastly Ca++ can be reabsorbed in the distal convoluted tubules and collecting duct via apical : calcium channels, as well as basolateral calcium pump Na, Ca++ exchangers.
165
When it comes to sodium reabsorption in the kidney:
a. ) Aldosterone increases Na + reabsorption in several transporters throught various parts of the kidney
b. ) Aldosterone stimulates Na+ reabsorption in the thick ascending limb through NKCC transporters
c. ) Aldosterone stimulates Na+ reabsorption as well as enhances K+ permeability on apical membrane in the collecting ducts.
d. ) The bulk of Na+ reabsorption occurs at the level of the distal convoluted tubule
c.) Aldosterone stimulates Na+ reabsorption as well as enhances K+ permeability on apical membrane in the
166
What do you need for renal blood flow calculation? Multiple answers present.
a. ) The renal plasma flow
b. ) Creatinine concentration in the urine
c. ) the hematocrit
d. ) Creatinine concentration in plasma
e. ) urine blood flow
a.) The renal plasma flow
+
c.) the hematocrit
167
Concerning renal blood supply, which of the following sequences are right?
a. ) peritubular capillaries -\> afferent arterioles -\> efferent arterioles
b. ) Afferent arteriole -\> glomerular capillaries -\> efferent arterioles
c. ) abdominal aorta -\> interlobar artery -\> arcuate artery
d. ) Afferent arteriole -\> efferent arteriole -\> glomerular capillaries
b.) Afferent arteriole -\> glomerular capillaries -\> efferent arterioles
168
Which one of the following has a filteribility of near zero?
a. ) Water
b. ) Hemoglobin
c. ) Glucose
d. ) Myoglobin
b.) Hemoglobin
169
Which one of the following is not a component of the filtration barrier?
a. ) Capillar endothelium
b. ) Bowmans capsule
c. ) Podocytes
d. ) Glomerular basement membrane
b.) Bowmans capsule
170
Which of the following mechanisms would cause GFR to decrease in response to decreased renal blood flow?
a. ) vasoconstriction of afferent arteriole
b. ) Vasodialation of afferent arteriole
c. ) vasoconstriction of efferent arteriole
d. ) dialation of the vasa recta
a.) vasoconstriction of afferent arteriole
171
The thyroid gland produces Which types of hormones?
The thyroid produces thyroid hormone ( T3/T4) (follicular cells) and Calcitonin (parafollicular cells).
172
What are the two molecules that are important for synthesizing thyroid hormones?
Iodine and Thyroglobulin
173
How is iodide transported into the thyroid follicle to synthesize thyroid hormones?
Iodine is sourced from food -\> transported in blood as iodide -\> through active transporter (of Na+/I- symporter) iodide gets into the cell and than pendrin transfers it into lumen.
174
How are T3 and T4 synthesized?
Iodine is sourced from food -\> transported in blood as iodide -\> through active transporter (of Na+/I- symporter) iodide gets into the cell and than pendrin transfers it into lumen. -\> Iodide and thyroglobulin will be oxidized via thyroid peroxidase -\> it becomes diiodotyrosine or monoiodotyrosine -\> 2 of these molecules get together ( if 2 diiodotyrosine get together than it is tetraiodothyrinine (T4) If 1 monoiodotyrosine and 1 diiodotyrosine get together than it is triiodothyronine (T3) -\> it then is endocytosed, and undergoes proteolysis within the cell. It is lastly transported out of cell to binding proteins to be transported via blood.
the amount of thyroid hormone free in plasma is mostly less than 1%.
175
How are T3 and T4 transported?
after being synthesized it then is endocytosed, and undergoes proteolysis within the cell. It is lastly transported out of cell to binding proteins to be transported via blood. It is lipid soluble and is transported in blood with plasma proteins. These include Thyroxine binding protein (TBG), Albumin, and Thyroxine- binding, prealbumin. Only free hormone is biologically attached.
176
How are thyroid hormones metabolized?
- Deiodination -\> Remove iodine ( main form) Mediated by 5'deiodinase
- Formation of hormone conjugates: Sulfates and glucuronides
- Modification of alanine moiety of the thyronine ( mediated by transamination or decarboxylation)
177
How do thyroid hormones execute their biological functions?
Lipid soluble -\> can penetrate cell membrane-\> T3 goes to nucleus and is bound to T3 receptor -\> complex is formed -\> Complex binds to DNA sequence ( called response element) -\> creates new proteins for biological function.
178
How is the synthesis of T3 and T4 regulated by the hypothalamus and pituitary gland?
Thyroid hormone synthesis is stimulated by TSH from the anterior pituitary gland. The anterior pituitary gland is given a message from the hypothalamus via TRH to secrete TSH. If there is too much TSH or TRH will cause negative feedback mechanism.
179
What are the common causes of hypothyroidism?
Primary:
- Lymphocytic thyroiditis -\> inflammation destroys thyroid
- Congenital: Thyroid dysgenesis -\> developed abnormally.
Secondary:
- Pituitary tumors -\> Tumor
- Radiation Therapy -\> decreased tissue function
- Ingestion of endogenous or exogenous glucocorticoids
( all of these are due to not enough pituitary hormone)
Tertiary:
- Hypothalamic tumors
- congenital as a result of TRH or TSH receptor defects
( these are because if deficit in thyrotropin release hormone.
180
What are the common clinical symptoms of hypothyroidism?
- Lethargy, obesity are the most common clinical signs. Difficult to diagnosis at first due to very mild symptoms in the beginning.
More pronounced symptoms ( later):
- Derm: Symmetrical truncal or tail head alopecia, thickened skin.
- Hair symptoms: Dull dry hair, poor hair regrowth after clipping. Puppy hair
- Cardiovascular signs (uncommon): Bradycardia, decreased cardiac contractility, atherosclerosis.
- Neuromuscular signs ( uncommon): myopathies, megaesophagus
- Neuropathies (uncommon): Bilateral or unilateral facial nerve paralysis, vestibular disease, lower motor neuron disorders
- Myxedema coma (unusual) : secondary to myxedematous fluid accumulations in brain and severe hyponatremia.
Others: Prolonged in-estrous intervals, silent heat, delivery of weak/ stillborn puppies, corneal lipid deposits, constipation.
181
How is hypothyroidism diagnosed?
- clinical signs,
- pathological findings ( anemia, hypercholesterol, hypernatremia, increased serum CPK. )
- Lab tests: decreased TT4 and TT3 concentrations. Reduced Free T4 (accuracy can be up to 90%), Increased TSH levels
- 100% accuracy doing all of these things
182
How is hypothyroidism treated?
Supplement thyroxine ( inexpensive) life long treatment.
183
How is hyperthyroidism diagnosed?
Elevated TT4, FT4 (can show elevated levels in early disease) T3 suppression test: Normal cats will have 50% suppression T4 due to negative feedback mechanisms. Diseased cats fail to respond to negative feedback mechanisms
184
How is hyperthyroidism treated?
Treatments:
- Sx ( difficult due to unknown qty to remove, scars, ect)
- Radioisotope iodine level -\> will destroy thyroid and become hypothyroid.
- Medication: Methimazole
185
What are the hormones secreted by the four layers of the adrenal gland?
Cortex:
- Zona Glomerulosa: Mineralcorticoids (aldosterone)
- Zona fasiculata: Glucocorticoids ( cortisol)
- Zona reticularis: (androgens)
Medulla: Catecholamines (epinephrine and norepinephrine)
186
What is the feature of the cells that secrete steroid hormone?
- Can synthesize steroids from cholesterols. Also can store in lipid droplets.
187
What are the primary functions of aldosterone in the renal tubule?
Fxn is to promote retention of Na+, secrete K + and H+ on the distal convoluted tubules. Na+ will increase blood pressure
188
What molecules stimulate the secretion of aldosterone?
increased Blood K+ and Angiotensin II
## Footnote
**\* Decrease in blood pressure.**
**\* Decrease in tissue fluid Na+ concentration.**
189
How is renin produced?
- Decrease NaCl activates p38 or ERK1/2 (transcription factors) which then stimulates COX-2 -\> COX-2 can stimulate PGE2 ( produced by distal tubule cells) which will bind receptor EP4 on the Juxtaglomerular cells (JGC) which alerts JGC that Na+ levels are low. JGC will produce renin.
190
What are the primary functions of glucocorticoids?
Fxn's to control metabolism
- Inc gluconeogenesis
- Inc use of glucose
- inc protein catabolism: -\> inc amino acids
- Inc GFR: inc water secretion
- Inc lipolysis
- Inc BP
- Inc Osteoclast activity
- Inc risk of infection/ suppression of immune status
191
How does ACTH stimulate the synthesis and secretion of cortisol?
- Stimulates LDL uptake
- Stimulate the hydrolysis of cholesterol esters to regenerate free cholesterol
- Enhance cholesterol transport into mitochondria.
- cAMP in cell will help cholesterol in mitochondria convert into pregneolone which will eventually be converted into cortisol and immediately released.
192
What are the three mechanisms that regulate glucocorticoid synthesis?
1. ) Feedback regulation
2. ) Circadian rhythm
3. ) Stress
Feedback Mechanisms:
Positive feedback:
- ACTH stimulates adrenal cortex to secrete cortisol.
- CRH stimulates anterior pituitary to secrete ACTH
Negative feedback:
- increase in cortisol causes hypothalamus to decrease CRH secretion, and decrease in ACTH secretion
193
How does low-dose dexamethasone suppression work in diagnosing hyperadrenocorticism (Cushing’s
syndrome)?
• LDDS Test:
◦ Normal animal: Low dose dex will decrease endogenous ACTH secretion and this will decrease circulating cortisol concentrations.
◦ Abnormal: They cannot decrease ACTH secretion
◦ 92-95% sensitivity at 8 hours, 5-8% of diseased dogs show suppression ( false negative)
194
How does the ACTH stimulation test work in diagnosing hyperadrenocorticism (Cushing’s syndrome)?
Animals with the condition will show an exaggerated response to exogenous ACTH.
195
What are the characteristic clinical signs of hyperaldosteronism (Conn’s Syndrome)?
Muscle weakness, cervical ventroflexion (head drop), hypertension, blindness, renal failure.
196
What are typical lab test results you may expect for hyperaldosteronism (Conn’s Syndrome)?
◦ Hypokalemia, decreased plasma K+ concentrations
◦ Hypernatremia, elevated plasma Na+ concentrations
◦ Metabolic alk (decreased H+ ( aldosterone increased secretion of hydrogen)
◦ Elevated CK
197
What are the precursor and cells for the synthesis of catecholamines?
Precursor: Tyrosine
2 kinds of chromaffin cells: one contains more epinephrine granules, one contains more norepinephrine cells.
198
How is the synthesis of catecholamines negatively regulated?
All of these mechanisms are feed back inhibition for TH. So TH is rate limiting enzyme.
199
How do different catecholamine receptors, when bound to epinephrine, initiate signal transduction inside a cell?
**\* Alpha 2: Inhibits adenyl cyclase, reducing cAMP (second messenger).**
**\* Beta: Activates adenyl cyclase, increasing cAMP (second messenger).**
* Alpha 1: activates PLC with PIP2-\> PLC will activate 2 second messengers, IP3 and DG (DAG?) -\> IP3-this promotes the calcium influx into the cell. DG - activates PK-C which will use calcium for protein synthesis and will activate transcription factors. This will create new proteins.
* Alpha 2 and Beta activates AC which uses ATP to make cAMP. This cAMP will activate protein kinase which will cause protein phosphorylation and activate transcription factors.
200
What are the primary functions of catecholamines?
◦ Glycogenolysis (increases): Breaks down glycogen into glucose, which will cause hyperglycemia.
◦ Gluconeogenesis: Needs a lot of glucose, so it will cause AA, LA, FA, glycerol into glucose to make more glucose.
◦ Lipolysis: Triglycerides will be made into glycerol and fatty acids which will be used to make more glucose
◦ Vasodilation in skeletal muscles will use FA to increase ATP production.
◦ HR will increase, contractility will increase and there will be vasodilation of coronary arteries.
◦ Vasoconstriction in gut, kidneys, and skin (non critical organs.
◦ you will have dilation of bronchial and increased respiration
201
The islets of Langerhans secrete which types of hormones?
* alpha cells: produces glucagon
* beta cells: produces insulin
* D cells: Somatostatin
* F cells: pancreatic polypeptides.
202
What is the structure of mature insulin?
**Chain A and Chain C connected by two disulfide bonds.**
203
How does hyperglycemia stimulate the synthesis and release of insulin in beta cells?
* Insulin independent channel -\> most cells rely on insulin to uptake glucose by cell.
* Glucose is also needed for Krebs cycle, when glucose is decreased, decreased ATP. When glucose increases there will be increased ATP production.
* When ATP is increased , ADP ratio closes K+/ATP channel causing cell depolarization.
* This will open voltage gate of calcium and cause increased insulin gene expression via CREB.
* Calcium will also release C peptide and insulin into the blood via exocytosis.
204
How does insulin reduce blood glucose?
* Fxn of insulin is to bring sugar into cells and turn into storage to remove from ECF
* This means their will be decreased glucose, FA and AA in the blood and they will be turned into storage forms
205
What are the main differences between type 1 and type 2 diabetes?
Type 1 Diabetes: 10% , most common in dogs, caused by destruction of Beta cells by immune cells, leading to insulin insufficiency.
• Insulin Responsive - Lifelong supplementation
• Genetic component: HLA-DR4
Type 2 Diabetes: 90 %, most common in cats, inability of cells to respond to insulin. Preventable.
- Insulin resistance
- Cause unknown : can be • B cell hypertrophy + hyperplasia
• Risk factors: overweight/ obese. Hypertension, physically inactive. Family history, genetic factor
In short:
• Type 1: insulin dependent (often lean but ~ 50% overweight/ obese. onset usually acute)
• Type 2: Non insulin dependent ( usually obese, subtle/ slow onset)
• Type 1 will have autoantibodies against insulin
206
How does diabetes cause major clinical symptoms, such as glycosuria, polyuria, dehydration, polydipsia,
weight loss, and polyphagia?
Increased glucose causes lipolysis (fat breakdown) and protein breakdown. This is because though there is an excess of glucose, the lack of insulin prevents the opening of the GLUT- 4 insulin dependent channels. Therefore the body looks for an alternative source of energy. This causes weight loss and hunger. Polyphagia -\> increased/ insatiable hunger. The glucose leaves in the urine, causing glucosuria. This will increase urine osmolality, increase urination (polyuria). This causes dehydration and increased thirst (polydipsia)
More water is needed to excrete glucose in urine which pulls it from ECF -\> this increases Osmolality in order to counterbalance the increased particle content.
207
What are the mechanisms underlying diabetic ketoacidosis (DKA)?
- Body will break down adipose tissue for fuel and the adipose tissue will be broken down to ketone bodies.
• Ketones will cause increase acidity of blood -\> ketoacidosis ◦ Fruity breath due to ketone bodies being converted to acetone.
208
How does glucagon activate intracellular signaling pathways?
Glucagon binds to cell surface receptor and activates intracellular second messenger to produce biological effects.
209
What are the main functions of glucagon in the liver and adipose tissues?
• Glucagon, binds to receptor, produces cAMP, which will activate PKaA and will cause gluconeogenesis, and glycogenolysis, as well as bind to pKA in fat cell, and will cause HSL to convert glycerol and FA which will be brought to liver \> this will increase glucose.
210
How does somatostatin suppress the beta-cell secretion of insulin and the alpha-cell secretion of glucagon?
Somatostatin blocks adenylate cyclase activity, suppressing Beta cell secretion of insulin and alpha cell secretion of glucagon in pancreas. Somatostatin binds to GPCR which decreases cAMP
211
How does somatostatin regulate stomach pH?
If pH is too low, D cells will produce somatostatin. This will inhibit production of HCl from parietal cells, which will then increase the pH. Somatostatin can also block histamine from going to the parietal cell and causing HCl secretion.
212
What is the function of the somatostatin produced by the hypothalamus?
Somatostatin that is produced by the hypothalamus will inhibit anterior pituitary secretion of growth hormones.
213
What is the distribution of calcium in the body?
* 1st largest pool- ~90% calcium in bone in form of hydroxyapatite crystals.
* 2nd largest pool : intracellular calcium mitochondria and ER
* Smallest pool : ECF (interstitial calcium and blood calcium.
214
What are the two primary calcium channels in the cell membrane and their controls?
* Voltage gated channels: Muscles and nerve cells. These are controlled by electric membrane potential.
* Ligand Gated channels: When ligand binds to receptor it opens channel. Most cells have this and is controlled by hormones and neurotransmitters.
215
How is calcium absorbed in the intestine?
absorption occurs by either passive diffusion: If there is high calcium content in the lumen. Or active transport when there is low calcium in the lumen. This is regulated by vitamin D.
216
How is calcium reabsorbed in the kidney?
• Ca++ reabsorbed at proximal tubules, then distal tubules then ascending loop of henlee.
217
What is the calcium distribution in the bone?
• soluble portion of bone ( amorphous crystal and soluble calcium) which is between osteoblasts and osteocytes. \*\*\*
218
What are the cell types in the parathyroid gland?
◦ Chief cells create PTH
◦ Oxyphil cells: Fxn's unknown
219
How do the Chief cells in the parathyroid gland sense calcium and magnesium levels to initiate the synthesis and release of PTH?
• Chief cells have a calcium sensor which, when decrease is detected it will cause release of PTH
220
What is the overall effect of PTH on calcium and phosphate metabolism?
Effect of PTH is to increase calcium and decrease phosphate.
221
What are the effects of PTH on amorphous bones?
◦ Transfer calcium across the osteoblast-osteocyte membrane
◦ No effects of phosphate concentrations in the blood
222
What are the effects of PTH on stable bones?
* PTH stimulates osteoblasts to secrete receptor activator of nuclear factor kappa b ligand ( RANK or RANK L). RANK L will activate Osteoclast precursor, which will create an active osteoclast.
* This will also cause inhibition of OPG or osteoprogesterin, which competes to bind with ligand, and will decrease the creation of osteoclasts.
223
What are the effects of PTH in the kidney?
* PTH will decrease Phosphate reabsorption in the proximal convoluted tubules.
* Ca++ reabsorption increases in the distal convoluted tubules.
224
How does PTH regulate the synthesis of the active vitamin D?
* PTH can promote the fxn of 1a - hydroxylase which will produce calcitriol. This will also be the reason 24-hydroxylase is produced which can also be formed because of high serum phosphate. The result is 24-25 (OH)2 D (inactive)
* 24- hydroxylase inactivates 1,25 (OH)2 D.
* feedback regulations. \*\*\*
225
How does the active vitamin D regulate calcium and phosphate metabolism?
1.) Ca++ absorption in intestine
2.) Ca++ absorption in kidney
3.) Ca++ and phosphate release in bone.
All will result in increase in calcium
226
What are the primary functions of calcitonin?
* Calcitonin counteracts the fxns of vitamin D and PTH.
* Inhibits osteoclasts and stimulates osteoblasts- decrease in mvmt of ca++ from labile bone calcium pool to the ECF.
* Inhibits Ca2+ absorption in the GI,
* Increases renal excretion of calcium and phosphate.
* This can lead to hypocalcemia and hyphosphatemia.
227
How does too much blood transfusion cause hypocalcemia?
When given too much blood (i.e transfusion) the blood product will have too much citrate and EDTA which can chelate Ca++ (or make it form a complex that is not absorbable
228
Why does hypocalcemia cause cells to be more excitable?
Sodium channels are unstable, cells more easily excited. Cells depolarize easier.
229
What are the characteristic clinical symptoms during hypocalcemia?
◦ Involuntary muscle contraction.
‣ Chvosteks sign: Twitch of facial muscles that occurs when gently tapping an individuals cheek in front of the ear.
‣ Trusseaus sign: Involuntary contraction fo muscles in hand. wrist ( i.e carpopedal spasm) this occurs after the compression of the upper arm with a blood pressure cuff.
◦ Tetany: involuntary muscle contraction
◦ Other: muscle cramps, abd pain, perioral tingling, seizures.
• Can cause arrhythmias ( torsades de pointes ( prolonged ST segment, prolonged QT)
230
How do you treat hypocalcemia?
Treatment: Normalize calcium
• give calcium gluconate
• supplement vitamin D
231
What are the common causes of hypercalcemia?
- acidosis
- Parathyroid overgrowth
- Malignant Tumors
- Excess vitamin D
232
How does acidosis cause hypercalcemia?
• Acidosis can cause hypercalcemia - this is because there is lots of protons, so the proteins available to bind calcium are decreased, leading to a relative increase in free calcium levels (hence hypercalcemia symptoms) and decreased bound calcium. However, total calcium levels can be normal.
233
What are the characteristic clinical symptoms during hypercalcemia?
* Can cause slower or absent reflexes (classic symptoms)
* Slow muscle contraction (constipation/ muscle weakness)
* Confusion, hallucination, stupor.
234
How does hypercalcemia cause kidney stones?
Hypercalciuria causes loss of fluid and dehydration. This will lead to formation of calcium oxalate stones.
235
How do you treat hypercalcemia?
* Treatment : Lower Ca2+ levels with medications
* Increase urinary excretion : Rehydrate ( more ca2+ filtered), Loop diuretics ( inhibit ca2+ resorption) Furosemide?
* Increase GI excretion ( glucocorticoids) -\> decrease calcium absorption.
* Prevent bone resorption: Bi-phosphates and calcitonin -\> inhibits osteoclasts
Physiology II
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