All kidney epithelia, including podocytes, rest on basement mem-

branes assembled into a planar surface through the interweaving of col-

lagen IV with laminins, nidogen, and sulfated proteoglycans. Structural

abnormalities in GBM associated with hematuria are characteristic of

several familial disorders related to the expression of collagen IV genes.

The extended family of collagen IV contains six chains, which are

expressed in different tissues at different stages of embryonic develop-

ment. All epithelial basement membranes early in human development

are composed of interconnected triple-helical protomers rich in α1.α1.

α2(IV) collagen. Some specialized tissues undergo a developmental

switch replacing α1.α1.α2(IV) protomers with an α3.α4.α5(IV) colla-

gen network; this switch occurs in the kidney (glomerular and tubular

basement membrane), lung, testis, cochlea, and eye, while an α5.α5.

α6(IV) network appears in skin, smooth muscle, and esophagus and

along Bowman’s capsule in the kidney. This switch probably occurs

because the α3.α4.α5(IV) network is more resistant to proteases and

ensures the structural longevity of critical tissues. When basement

membranes are the target of glomerular disease, they produce moder-

ate proteinuria, some hematuria, and progressive kidney failure.

gbmd