Pathogenesis of Focal Segmental Glomerulosclerosis Caused by a Leu754Val Mutation in ARHGAP32

Focal segmental glomerulosclerosis (FSGS) shows a poor response to Hormones and Other treatment schemes and rapidly progresses to end-stage renal disease. Genetic factors are important causes of FSGS. We recently identified a new candidate pathogenic ARHGAP32 mutation in a family affected by FSGS and further investigated its functional impact through in vivo and in vitro studies. We established in vitro models of ARHGAP32 overexpression in podocytes and COS-7 kidney cells by plasmid transfection. Mice with the point mutation were established using CRISPR/Cas9 technology, followed by the establishment of a kidney injury model by adriamycin administration via the tail vein. The ARHGAP32 protein was found to be expressed in human kidney tissues. Podocytes transfected with mutant ARHGAP32 showed a significant decrease in the expression of the podocyte markers nephrin. Similarly, COS-7 cells transfected with mutant ARHGAP32 showed decreased expression of the cytoskeletal protein F-actin. The ARHGAP32 mutant protein had 20-fold higher affinity for Cdc42 than the wild-type protein. Adriamycin-induced L405V mutant mice showed slow growth, proteinuria, increased serum creatinine and blood urea nitrogen levels, and pathological kidney damage. RhoA, Rac1, and Cdc42 all showed decreased expression in podocytes overexpressing mutant ARHGAP32 and in the kidneys of mutant mice. These findings suggest that the ARHGAP32 L754V mutation induces podocyte damage, leading to kidney damage and the potential development of FSGS. This study provides a new basis for elucidating the pathogenesis of FSGS and the exploration of new therapeutic measures.

ARHGAP32; focal segmental glomerulosclerosis; gene mutation; pathogenesis; podocyte.