Renal Physiology II Flashcards by Joel Glotfelty

Note that constriction of the efferent arteriole will cause

Back pressure within the glomerulus

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In a healthy nephron, any increase in pressure within the glomerulus will increase

GFR

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Low resistance and relatively high pressure environment when compared to that of the systemic capillary network

Between afferent and efferent ends of glomerulus

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The combination of low resistance, high pressure (50 mmHg), and enormous surface area of the glomerulus enables the filtration of approximately

180 L of plasma per day

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Regulated by the same SNS norepinephrine-adrenoreceptor-dependent mechanism of action that occurs in peripheral vascular smooth muscle

Flow within afferent arteriole

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Functions via the intricate concerted actions of the SNS, natiuretic peptides, paracrine factors, and the RAAS

Autoregulation of afferent arteriole flow

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Via autoregulation, a fairly narrow range of GFR and RBF can be maintained even in the face of markedly changing

MAP

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Occurs in response to 1.) pressure-induced distension of both vascular smooth muscle and the vascular endothelium within the afferent arteriole, and 2.) the tubular glomerular feedback system

Autoregulation

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Pressure-induced distension of both vascular smooth muscle and the vascular endothelium within the afferent arteriole is essentially just

Stress induced activation of cation channels, depolarization, Ca2+ influx, and contraction

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Uses feedback between several components of the nephron and its microvasculature

Tubular-glomerular-feedback (TGF) system

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Regulated by the concentrations of Na+ (or NaCl) in the forming urine as it reaches the cortical thick ascending limb (TAL)

TGF System

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In this region of the TAL, there is a population of specialized cells collectively known as the

Macula Densa

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These macula densa cells are in close approximation with the

Juxtaglomerular (JG) apparatus

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Imbedded around the afferent arteriole

JG apparatus

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The JG apparatus contains JG cells (modified smooth muscle cells) that secrete

Renin

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As GFR is increased to the upper physiologic limits, we see

Lots of H2O and NaCL in the forming urine

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This increased urine NaCl load traverses the nephron to the region of the

Macula Densa

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At the macula densa, NaCl delivery (a signal for elevated GFR) stimulates the depolarization of

Macula ensa cells

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Upon activation, these macular cells secrete many factors including ATP, adenosine, and thromboxane, each of which target and promote

Vasoconstriction of the afferent arteriole

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Vasoconstriction of the afferent arteriole lowers glomerular P, which down-modulates

GFR

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In the event of exxagerated volume expansion (increased ECF volume), the sensitivity of the TGF mechanism is decreased because the result of increased GFR is a substantial increase in

H2O and Na+ filtration (pressure natriuresis)

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There is lots of Na+ in the filtrate, but there is a lot more H2O, thus the lumenal [Na+] is relatively

Low

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Under these conditions, what is the consequence of the relatively low lumenal [Na+]?

The TGF mechanism is more or less desensitized

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This sustains a higher

Glomerular P

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The higher glomerular P causes increaed GFR, and therefore promotes a higher volume of urine excretion in order to promote

Restoration of BP

In summary, the TGF mechanism is an acute regulator of

GFR

By using Na+ in forming urine as a marker of GFR, the TGF system indirectly interprets volume-pressure status using glomerular pressure and filtration and modulates GFR by controlling

Afferent smooth muscle tone

What are the most important hormones for regulation of renal function?

The members of the RAS, arginine vasopressin (ADH or vasopressin), atrial natriuretic peptide (ANP), norepinephrine, and aldosterone

The only one of these hormones that does not have a direct role in the control of GFR and RBF (renal blood flow) is

Aldosterone

A key component of renal function, and this begins with the mediation of renal organogenesis in utero

Renin-Angiotensin System (RAS)

Throughout life, the RAS functions via endocrine, paracrine, and autocrine mechanisms to modulate

Renal BP and thus regulate GFR

Renal Na+ reabsorption is also modulated by

An-II

A potent vasoconstrictor

An-II

The relatively inert precursor hormones of An-II are

Angiotensinogen and An-I

All components of the RAS are expressed in the

Kidney

Expressed within proximal tubule cells

Angiotensinogen

Present within the proximal tubule brush border

Angiotensin converting enzyme (ACE)

There is also an extrarenal RAS system. This system still depends upon renin from JG secretionm but the angiotensinogen is produced and secreted by

Hepatocytes

Expressed in renal and cardiac tissues where it converts An-II into angiotensin 1-7

ACE2

angiotensin 1-7 binds to Mas, a G-protein coupled receptor, to stimulate

Vasodilation, block proliferation, and promote bradykinin production

Angiotensin 1-7 has actions which counter those of

An-II

Angiotensinogen is targeted by

Renin

A protein hormone that is produced and secreted by the JG cells

Renin

Renin secretion is regulated by which 5 things?

1. ) SNS tone (JG cells have B1 adrenoreceptors) 2. ) Distension of afferent arteriolar endothelium (elevated BP) 3. ) Signals from macula densa 4. ) ANP 5. ) Negative feedback by An-II

Renin catalyzes the conversion of angiotensinogen into

An-I

The conversion of angiotensinogen into the An-I is the basis for the -An indicator of RAS activity

Plasma Renin Activity (PRA) assay

Volume depletion leads to lowered BP. This would cause secretion of Renin with asubsequent increase in

PRA

Volume increase leads to elevated BP and the shut off of the

RAS (decreased PRA)

Catalyzes the conversion of An-I to An-II and also the degredation of bradykinin into inactive peptide fragments

Angiotensin Converting Enzyme (ACE)

Bradykinin functions as a

Vasodilator

This, ACE supports vasoconstriction in which two ways?

1. ) Production of An-II | 2. ) Degredation of bradykinin

During periods of hypovolemia such that normal perfusion pressure can not be maintained, signals are sent to mobilize the

RAS

An-II induces vasoconstriction of systemic arterioles. This raises

An-II dependent constriction of the efferent arteriole steadies

Glomerular P

With constriction of the efferent arterioles by An-II, renal perfusion is reduced leading to lowered P within the

Peritubular capillaries

This enables increased reabsorption of

Na+ and H2O

An-II binds two members of the seven transmembrane G-protein-coupled receptor family known as

AT1 and AT2

Expressed within the smooth muscle of afferent and predominantly efferent arterioles, renal tubules, and peripheral vasculature -Predominant AT receptor expressed in humans

AT1

In the event of diminished ECV, An-II binds and activates AT1 within the

Efferent arteriole vascular smooth muscle

This induces efferent vasoconstriction and maintains glomerular pressure in order to sustain optimal ultrafiltration across the

Glomerular capillaries

AT1 is also expressed within renal tubules and cells within the

Adrenal zona glomerulosa

Studies in mice have shown that AT1 activity is coupled to the activation of the transporters NHE3, NKCC, NCC, and ENaC, all of which enable

Na+ reabsorption

The main stimulus for aldosterone production and secretion in the adrenal cortex

An-II

AT1 is regionally expressed within the

Renal tubule epithelium and JG cells

Has the ability to both up and down regulate the RAS

An-II

Known to mediate An-II dependent vasoconstriction in the renal efferent arterioles and An-II stimulated Na+ reabsorption from the tubules

AT1

Represents a multileveled feedback-dependent control mechanism for mediating

GFR and Na+ reabsorption

What are three pharmalogical mechanisms designed to target the RAS

1. ) ACE inhibitors (enalapril) 2. ) ARBs (losartan) 3. ) Renin inhibitors (aliskiren)

Has been localized to lung, renal coronary, myocardial tissues, as well as cardiac fibroblasts in the adult -prevalent during fetal organogenesis

AT2

Experimental evidence indicates that AT2 mediates

Vasodilation and natriuresis

Within renal vascular smooth muscle, promotes the nitric oxide synthase-mediated production of nitric oxide, activation of guanylyl cyclase, the subsequent generation of cGMP

AT2

The nitric oxide synthase-mediated production of nitric oxide, activation of guanylyl cyclase, and the subsequent generation of cGMP is a signaling motif that promotes

Vasodilation

The activation of AT2 can also induce

Bradykinin secretion (a vasodilator and natriuretic factor)

Therefore, the effectos of an ARB may be multi-tierd by

1. ) Direct block of AT1 mediated vasoconstriction and Na+ reabsorption 2. ) Promoting AT2 release of bradykinin 3. ) Promoting AT2 dependent vasodilation and natriuresis

A renin inhibitor that binds with high specificity to the proteolytic active sites within renin and thus blocks its activity

Aliskiren

If renin and/or ACE is blocked, then we disrupt the production of

An-II

Thus, renin and ACE inhibitors can allevite which effects of An-II

An-II's vasoconstrictive and antinatriuretic effects

In addition, an ACE inhibitor will prevent the ACE-dependent degradation of

Bradykinin

Renin and ACE inhibitors will also tend to lower levels of which hormone?

Aldosterone

However, there are ACE independent pathways for synthesis of

An-II -ACE independent pathways account for 40% of intrarenal An-II

Also, when An-Ii production is impaired, we actually lose the short loop feedback inhibition of renin. Thus,

Renin activity (measured as PRA) actually increases

This phenomenon is referred to as the

ACE escape

PREganglionic SNS fibers innervate the

Adventitia of renal arteries, tubules, and JG apparatus

POSTganglionic SNS fibers secrete

Norepinephrine

Targets both the afferent and efferent arterioles

Norepinephrine

Activates post-junctional a1 adrenoreceptors within vascular smooth muscle

Norepinephrine

The resulting vasoconstrictive action induces a collective reduction in -maintains plasma volume

GFR and renal perfusion

Norepinephrine also stimulates renin secretion from JG cells by binding

B1 adrenoreceptors

Elevated SNS activity can enhance some degree of H2O and Na+ reabsorption from tubules via

a2 adrenoreceptors

Thus the collective pattern of increased SNS activity is the

Production of An-II,m conservation of plasma volume by slowing GFR, and enhancing Na+ and H2O reabsorption

A protein hormone that is secreted by neurons that terminate within the posterior pituitary

Arginine Vasopressin (AVP, aka ADH or vasopressin)

AVP is the neuroendocrine hormone that induces the renal-dependent conservation of plasma volume by stimulating

H2O and Na+ reabsorption

AVP also functions as a

Vasoconstrictor

In response to hypoosmolality, osmoreceptors within the neurons of the organus, vasculosus lamina terminales are

Activated

Activation of these osmoreceptors initiates a signal that causes the nerve termini within the posterior pituitary to secrete

AVP

AVP stimulates vasoconstriction within the renal microcirculation and peripheral arterioles by binding to the

V1a receptor isoform

Within the nephron, AVP binds the V2 receptor isoform where it promotes

H2O reabsorption.

AVP promotes H2O reabsorption by inducing the expression and activation of

Aquaporin protein-2 (AQP2)

Also increases the rate of active Na+ reabsorption from the TAL and DCT via its effects on NKCC (TAL), NCC (DCT), and the tubule epithelial Na+ channel (ENaC) (DCT)

AVP

The third isoform of AVP receptor that is expressed in the anterior pituitary, and activation of this receptor is coupled to the secretion of adrenocorticotropic hormone (ACTH)

V1b

Renal Physiology II Flashcards

(100 cards)