Figure 8.

Proposed model: Loss of Crb2 expression at the SD is critical for podocyte injury in Crb2podKO and human CRB2 mutations. (A) In healthy glomeruli, podocytes foot processes (FPs) are interdigitating with each other and form adjacent Crumbs2 (green) and Nephrin (red) clusters at the slit diaphragm. (B) Crb2 loss at the slit diaphragm due to genetic inactivation (in Crb2 ^podKO mice) or due to dysfunctional Crb2 export to the cell surface (in patients with CRB2-related SRNS) prevents an interaction between Crb2 and Nephrin and destabilizes Crb2 cluster formation at the slit diaphragm. In podocytes, this results in increased formation of effaced and disorganized FPs, accompanied by enhanced appearance of tight junction–like (electron-dense) structures. In addition, in case of CRB2 mutants, misfolded Crb2 proteins can induce an ER stress response in podocytes (pink lightning). In summary, ER stress–linked cell damaging and slit diaphragm composition injury cause proteinuria that later results in glomerular sclerosis and renal failure. SD, slit diaphragm.