Podocytopathies range from rare genetic diseases, such as congenital nephrotic syndrome, to common acquired conditions, such as hypertensive nephropathy. Focal segmental glomerulosclerosis (FSGS) is a histologically defined podocyte disease with both genetic and acquired causes. In FSGS, podocyte damage occurs, leading to foot process effacement, proteinuria, and progressive podocyte loss, ultimately resulting in glomerulosclerosis.

Podocytes form the most selective component of the glomerular filtration barrier. They have primary foot processes that branch into numerous interdigitating secondary foot processes, creating a network surrounding the glomerular capillaries. These secondary foot processes are separated by the filtration slit, which is bridged by the so-called slit diaphragm—a specialized cell–cell junction formed by an interacting protein network. Proteins such as nephrin, podocin, and the intracellular components CD2AP and ZO-1 form the slit diaphragm complex in podocyte foot processes (H. Pavenstädt et al., Physiol Rev, 2003).

The mechanical forces acting on podocytes are counterbalanced by the actin cytoskeleton in their foot processes. Almost all podocyte diseases are characterized morphologically by a foot process effacement associated with actin cytoskeleton remodeling. In recent years, approximately 40 monogenic mutations have been identified that lead to FSGS. Some of these monogenic podocytopathies are caused by mutations in actin-associated proteins expressed in podocytes, such as ACTN4, INF2, MYO1E, MYH9, and ANLN. These mutations lead to varying disruptions in podocyte function, many of which remain poorly understood.

Mutations in INF2 are the most common cause of autosomal dominant FSGS (C. Schell und T.B. Huber, J Am Soc Nephrol, 2017; D. Feng et al., Am J Physiol, 2018). The group of R. Wedlich-Söldner recently demonstrated that INF2 plays a crucial role in calcium-mediated actin reorganization (CaAR) in cells (P. Wales et al., Elife, 2016). ). Interestingly, disease-associated INF2 variants cause persistent actin reorganization in cultured podocytes, Drosophila melanogaster nephrocytes, and primary urine-derived cells from patients carrying INF2 mutations (S. Bayraktar et al., J Am Soc Nephrol, 2020). This actin reorganization may serve as a useful readout for systematically analyzing INF2-related mutations.

In the coming years, we aim to investigate whether INF2-related repair processes in podocytes can be stimulated and to determine the in vivo function of INF2 in podocyte biology. To this end, we have generated a podocyte-specific INF2 knockout mouse.

(DFG project number 194468054)