L21 – Molecular Composition and Functions of Glomerular barrier Flashcards Preview

MBBS I CPRS > L21 – Molecular Composition and Functions of Glomerular barrier > Flashcards

Flashcards in L21 – Molecular Composition and Functions of Glomerular barrier Deck (52):
1

What are basement membranes?

Specialized ECM that underlie all epithelial cell sheets and tubes

2

What does basement membrane Provide strong connection between?

epithelia and underlying connective tissue

3

What three core components make up basement membrane?

Type IV collagen
Proteoglycans
Laminin (glycoprotein)

4

What does BM act as in glomerular?

Filtration barriers between parenchymal cells and connective tissue space

5

What is the normal GFR range?

90-140mL/min

6

What is normal Plasma / blood flow rate from renal arteries (Qp) ?

~700 mL/min

7

What are the 3 Structures that govern transport processes at the glomerular barrier?

Fenetrated glomerular endothelial surface

Glomerular Basement membrane

Podocyte foot processes

8

What is name of space between podocyte foot processes?

Slit Diaphragm

9

Fenestrated glomerular endothelial surface (ESL) other name?

Glycocalyx

10

What is ESL formed by?

Secreted proteoglycans

Secreted glycosaminoglycans
(GAG)

Adsorbed plasma proteins

11

What is the function of Chondroitin sulfate in ESL?

Negative charge on surface = barrier to prevent passage of charged molecules

12

What makes up most Proteoglycans found on ESL?

Syndecan core protein + Chondroitin sulfate/ Heparan Sulphate side chains

Glypican core protein + Heparan sulphate side chain + GPI anchor

13

How can podocytes produce chemicals that affect endothelial glycocalyx?

Podocyte produces :
ang1 >VEGFR1
VEGF > VEGFR2

14

Chemicals that allow Endothelial glycocalyx to interact with GBM?

a5b1, a5b3

15

How are collagen molecules arranged?

3 polypeptide chains (α-chains) form triple helix

16

What is aa sequence of collagen?

repeating triplet sequence “Gly-X-Y” (X, Y = amino acids other than glycine)

17

Why is glycine in every third position on collagen chain?

small enough to fit into restricted space in center of triple helix, allow tight twisting

18

What are the 4 steps to intracellular biosynthesis of Type IV collagen?

Pre-procollagen chains are translated

Cleavage of signal peptides to form procollagen α chains

Hydroxylation, Glycosylation

Association of nascent carboxy-terminal propeptide chain (coil around each other)

19

How is pre-procollagen translated and translocated into ER?

guided by signal peptides to
translocate into ER lumen for intracellular modification

20

How happens to pre-procollagen to turn into procollagen?

Cleavage of signal peptides (so that they do not go elsewhere after entering lumen of ER) > form procollagen α chains

21

What intracellular modifications are made before the procollagen form triple helix?

Hydroxylation of certain proline, lysine residues

Glycosylation (add galactose, glucose) of: hydroxylysine, asparagine residues

22

How is triple helix of collagen stabilized?

Association of nascent carboxy-terminal
propeptide chain (coil around each other)
= stabilize with S-S bond > triple helical procollagen

23

What supramolecular assembly of Type VI collagen takes place after being exported from cell? (tropocollagen to triple helical domains)

tropocollagens dimerize at Carboxy terminal terminals (NC1) > form tropocollagen dimers

4 tropocollagen dimers aggregate at N-terminal > form type IV collagen tetramer (7S domain)

Lateral association of triple helical domains

24

What does the structure of collagen do for filtration?

Has big spaces in
between structures for filtration

25

What is the structure of laminin?

Contains A, B1 and B2 chains > join to form a 4-
armed structure (= one laminin molecule)

26

What causes laminin molecules to join up?

In the presence of Ca2+, free ends join respective
partners at C-terminal, form polymers/network

27

What is Laminin always associated with?

Entactin
Nidogen

28

How does proteoglycan associate with Laminin and type IV collagen?

Fill spaces between laminin and collagen

29

What is the glyco- part of Basement membrane (BM)-type Proteoglycans?

heparan sulphates (HS)

30

How many Heparan Sulphates link to polypeptides?

Linked to serine residues of
polypeptides, e.g.:
 2 HS per agrin (spread out)
 3 HS per perlecan (clustered at one end)

31

What other protein can HS form a preteoglycan with?

Chondroitin

32

How does HS on Agrin contribute to the structure of the proteoglycan?

HS has negative charge

-ve charges cannot cluster, so proteoglycan extends

33

Type IV collagen, proteoglycans and Laminin form what?

BM Scaffold

34

What is the first layer of ECM?

laminin polymers anchored to membrane associated receptor proteins

35

How is Laminin polymer in ECM anchored to the membrane?

Associated receptor proteins

1. Integrins
2. α-dystroglycans
3. Sulfatides

36

How does Type IV collagen add to Laminin polymer in ECM?

 Bridged by nidogen/entactin (associated with Laminin)
or
 Direct interaction

37

How does proteoglycans interact with Collagen and Laminin in ECM? (think about the two types of proteoglycan and their attachments)

Proteoglycans :
1) HS + Agrin = bind to cell surface receptor proteins (e.g. sulfatides) and Laminin

2)HS + Perlecan bind to cell surface receptor proteins and interact with NC1 domain of tropocollagen
dimers

or

Interact with 7s domain of type IV collagen tetramer

38

How does Laminin + collagen filter molecules passing by?

Overall negative charge
Filter by size, charge:
 Positive = trapped
 Negative = repelled
If Protein is big and negatively charged = hard to get through

39

What is the key component of Slit diaphragm, the space between the podocte foot processes? How can it be visualized?

Key component = nephrin molecules

visualize by immunostaining
technique: gold-linked antibodies bind to nephrin

40

What composes nephrin in slit diaphragm?

From inside cell to further outside cell:

 Intracellular domain (C-terminal)
 Fibronectin type III domain
 8 immunoglobulin-like domains (N-terminal) containing 1 Spacer domain

41

What allows the immunoglobins in nephrin to be stabilized (except spacer domain)?

Cysteine forms
stable S-S covalent bonds > form loops (except
in spacer domain: single cysteine = no loop)

42

How does nephrin network change shape?

Receive signal: cytoskeletal proteins (actin) pull in / out the interdigitating nephrin molecules from 2 opposite foot processes

43

Mutation in what results in proteinuria/ nephrotic syndorme?

Mutations in nephrin / its intracellular interacting
partners (CD2AP, podocin)

44

Is the change in concentration of small solutes significant after filtration?

Filtration produces no significant changes in concentration of small solute

45

How does nephritis change ultrafiltration?

loss of charge selectivity
Affect nephrin, GBM components, only sort by size of molecule, not charge

46

What charge molecules are filtered more (more go through to Bowman's capsule)?

Positive charge molecules filter through more than negative charge

47

What is used to test nephritis effect on charged molecule filtration?

Dextran - neutral
Dextran sulphate - -ve
DEAE Dextran - +ve

48

What is Alport syndrome a deficiency in ?

Alport syndrome: deficient
assembly of the a3-,4-,5-
collagen type IV network

49

What does diabetic glomerulopathy affect?

Thickened GBM
Decreased HS proteoglycans

50

What does minimal change nephrotic syndrome affect ( laminin β2-deficient) ?

Reduction of polyanionic sites, HS


51

What causes urinary excretion of GBM HS proteoglycan?

Post-exercise proteinuria:
> Temporary decrease in charge of the GBM > Urinary excretion of GBM HSPG

52

How does Glomerulonephritis change BM and ECM?

thickened mesangial BM and matrix

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