Upregulation of c-mip is closely related to podocyte dysfunction in membranous nephropathy

Abstract

Membranous nephropathy is a glomerular disease typified by a nephrotic syndrome without infiltration of inflammatory cells or proliferation of resident cells. Although the cause of the disease is unknown, the primary pathology involves the generation of autoantibodies against antigen targets on the surface of podocytes. The mechanisms of nephrotic proteinuria, which reflect a profound podocyte dysfunction, remain unclear. We previously found a new gene, c-mip (c-maf-inducing protein), that was associated with the pathophysiology of idiopathic nephrotic syndrome. Here we found that c-mip was not detected in the glomeruli of rats with passive-type Heymann nephritis given a single dose of anti-megalin polyclonal antibody, yet immune complexes were readily present, but without triggering of proteinuria. Rats reinjected with anti-megalin develop heavy proteinuria a few days later, concomitant with c-mip overproduction in podocytes. This overexpression was associated with the downregulation of synaptopodin in patients with membranous nephropathy, rats with passive Heymann nephritis, and c-mip transgenic mice, while the abundance of death-associated protein kinase and integrin-linked kinase was increased. Cyclosporine treatment significantly reduced proteinuria in rats with passive Heymann nephritis, concomitant with downregulation of c-mip in podocytes. Thus, c-mip has an active role in the podocyte disorders of membranous nephropathy.

Expression patterns of RelA and c-mip are associated with different glomerular diseases following anti-VEGF therapy

“…35 In addition, Cyclosporin inhibits c-mip expression and reduces proteinuria in an experimental model of nephrotic syndrome. 36 These results suggest that c-mip has a crucial role in podocyte dysfunction leading to proteinuria. Renal TMA is a serious complication that usually leads to drug withdrawal.…”

Induction of C-Mip by IL-17 Plays an Important Role in Adriamycin-Induced Podocyte Damage

“…Up-regulation of c-mip has been reported in several glomerular diseases and some experimental kidney diseases [6,19,20]. In this study, we investigated the expression change of c-mip in peripheral blood mononuclear cells (PBMC) and kidney tissues from AN mice.…”

“…Recently, increased expression of c-maf inducing protein (c-mip) was found in podocyte as a mechanism for podocyte injury and proteinuria in both human and experimental kidney diseases [6,7,19,20]. Initially, c-mip was identified in lymphocytes of NS patients experiencing a relapse [7].…”

c-Maf inducing protein inhibits cofilin-1 activity and alters podocyte cytoskeleton organization

“…Expression of CMIP, a novel podocyte protein, is induced in human and murine minimal change disease and membranous nephropathy, and in angiotensin II, lipopolysaccharide and ADR-induced podocyte damage (5,8,9,20). In the present study, CMIP expression was examined in a common podocyte damage model induced by PA.…”

“…The specific transgenic mice, with CMIP present in podocytes, demonstrated massive proteinuria and developed foot process effacement (5). Expression levels of CMIP were observed to be increased in passive-type Heymann nephritis and adriamycin (ADR)-induced nephropathy (8,9). In addition, the abundance of CMIP was enhanced in interleukin (IL)-17-induced podocyte damage (9).…”