Asparagine endopeptidase protects podocytes in adriamycin-induced nephropathy by regulating actin dynamics through cleaving transgelin

Focal segmental glomerulosclerosis (FSGS) is the most common glomerular disorder causing end-stage renal diseases worldwide. Central to the pathogenesis of FSGS is podocyte dysfunction, which is induced by diverse insults. However, the mechanism governing podocyte injury and repair remains largely unexplored. Asparagine endopeptidase (AEP), a lysosomal protease, regulates substrates by residue-specific cleavage or degradation. We identified the increased AEP expression in the primary proteinuria model which was induced by adriamycin (ADR) to mimic human FSGS. In vivo, global AEP knockout mice mani-fested increased injury-susceptibility of podocytes in ADR-induced nephropathy (ADRN). Podocyte-specific AEP knockout mice exhibited much more severe glomerular lesions and podo-cyte injury after ADR injection. In contrast, podocyte-specific au-gmentation of AEP in mice protected against ADRN. In vitro, knockdown and overexpression of AEP in human podocytes re-vealed the cytoprotection of AEP as a cytoskeleton regulator. Furthermore, transgelin, an actin-binding protein regulating actin dynamics, was cleaved by AEP, and, as a result, removed its actin-binding regulatory domain. The truncated transgelin regulated podocyte actin dynamics and repressed podocyte hy-permotility, compared to the native full-length transgelin. To-gether, our data reveal a link between lysosomal protease AEP and podocyte cytoskeletal homeostasis, which suggests a poten-tial therapeutic role for AEP in proteinuria disease.

Automated summary

Focal segmental glomerulosclerosis (FSGS) is the most common glomerular disorder causing end-stage renal diseases worldwide. Our study found that increased expression of lysosomal protease AEP protected podocytes from injury by regulating the homeostasis of the cytoskeleton.