Isoform switching of type IV collagen is developmentally arrested in X-linked Alport syndrome leading to increased susceptibility of renal basement membranes to endoproteolysis.
Normal glomerular capillaries filter plasma through a basement membrane (GBM) rich in alpha3(IV), alpha4(IV), and alpha5(IV) chains of type IV collagen. We now show that these latter isoforms are absent biochemically from the glomeruli in patients with X-linked Alport syndrome (XAS). Their GBM instead retain a fetal distribution of alpha1(IV) and alpha2(IV) isoforms because they fail to developmentally switch their alpha-chain use. The anomalous persistence of these fetal isoforms of type IV collagen in the GBM in XAS also confers an unexpected increase in susceptibility to proteolytic attack by collagenases and cathepsins. The incorporation of cysteine-rich alpha3(IV), alpha4(IV), and alpha5(IV) chains into specialized basement membranes like the GBM may have normally evolved to protectively enhance their resistance to proteolytic degradation at the site of glomerular filtration. The relative absence of these potentially protective collagen IV isoforms in GBM from XAS may explain the progressive basement membrane splitting and increased damage as these kidneys deteriorate.
Kalluri
R
R
Penn Center for Molecular Studies of Kidney Diseases, Renal Electrolyte and Hypertension Division, University of Pennsylvania Medical School, Philadelphia, Pennsylvania 19104-6144, USA.
Shield
C F
CF
Todd
P
P
Hudson
B G
BG
Neilson
E G
EG
D001485:Basement Membrane / Q000378:metabolism; D002401:Cathepsin B / Q000378:metabolism; D056649:Cathepsin G; D002403:Cathepsins / Q000378:metabolism; D002852:Chromatography, Ion Exchange; D003094:Collagen / Q000096:biosynthesis* / Q000302:isolation & purification; D017364:Collagenases / Q000378:metabolism; D005314:Embryonic and Fetal Development; D010450:Endopeptidases / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D007668:Kidney / Q000196:embryology / Q000254:growth & development / Q000378:metabolism*; D007672:Kidney Cortex / Q000378:metabolism; D007678:Kidney Glomerulus / Q000378:metabolism*; D008297:Male; D009394:Nephritis, Hereditary / Q000235:genetics / Q000378:metabolism*; D010196:Pancreatic Elastase / Q000378:metabolism; D012016:Reference Values; D012697:Serine Endopeptidases; D014960:X Chromosome
D003094:Collagen; D002403:Cathepsins; D010450:Endopeptidases; D012697:Serine Endopeptidases; C534094:CTSG protein, human; D056649:Cathepsin G; D010196:Pancreatic Elastase; D002401:Cathepsin B; D017364:Collagenases