L21: Molecular Composition And Functions Of Glomerular Barrier

Question 1

Components of filtration barrier

Answer 1

1. Fenestrated endothelium
2. Fused basement membrane
3. Podocytes / Filtration diaphragm

Question 2

Slit diaphragm / filtration slit

Answer 2

1. Nephrin (3 domains: cytoplasmic, transmembrane, extracellular: stabilised by disulphide bond)
2. Podocin (CD2AP)

Question 3

Components of GBM

Answer 3

1. Type IV collagen (basal lamina)
—> network
—> C-terminal Dimerisation
—> N-terminal Tetramerisation
—> lateral association of triple helix

2. Laminin (glycoprotein)
   —> A, B1, B2 chains —> 4-armed structure (free ends to join others)
   —> monomer —> oligomer —> polymer
3. Proteoglycan (BM-type Heparan sulfate proteoglycan HSPG)
   —> Agrin + Perlecan
   ***—> -ve charged heparan side chains —> repel albumin/plasma proteins

Question 4

Intracellular biosynthesis of Type IV collagen

Answer 4

translation of mRNA
—> pre-procollagen
—> cleavage of signal peptide
—> procollagen α chains
—> hydroxylation, glycosylation, C-terminal propeptide stabilised by Disulphide bond
—> procollagen triple helix (Gly-X-Y, proline/hydroxyproline, lysine/hydroxylysine)

Question 5

Components of fenestrated endothelial barrier

Answer 5

Glycocalyx (Hyaluronan, glycoprotein, glycolipid, Heparan sulphate)

Question 6

Proteinuria

Answer 6

Microalbuminuria: 30-300 mg/day
Proteinuria: > 300 mg/day
Nephrotic syndrome: > 3.5 g/day
Albumin / creatinine: 30 ug/mg

Question 7

Defective barrier in relation to biochemical changes

Answer 7

Alport syndrome:
Deficient assembly of α3, α4, α5 collagen type IV network

Diabetic glomerulopathy:
Thickened GBM with decreased HSPG (low in agrin/perlecan)

Minimal change nephrotic syndrome:
Reduction of polyanionic sites + HS / laminin β2 deficient

Post-exercise proteinuria:
Temporary decrease in GBM charge + urinary excretion of HSPG