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Mechanism of Kemeng Fang's Inhibition of Podocyte Apoptosis in Rats with Membranous Nephropathy through the PI3K/AKT Signaling Pathway
Published on: August 23, 2024
Upregulation of c-mip is closely related to podocyte dysfunction in membranous nephropathy
Kelhia Sendeyo1, Vincent Audard, Shao-yu Zhang
1INSERM, U 955, Equipe 21, Créteil, France.
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.
Insights
C-maf-inducing protein (c-mip) plays a key role in membranous nephropathy, a kidney disease causing nephrotic syndrome. Its overexpression in podocytes is linked to proteinuria and can be reduced by cyclosporine, suggesting a therapeutic target.
Area of Science:
- Nephrology
- Molecular Biology
- Immunology
Background:
- Membranous nephropathy is characterized by nephrotic syndrome due to podocyte dysfunction.
- Autoantibodies against podocyte antigens are implicated, but proteinuria mechanisms are unclear.
- C-maf-inducing protein (c-mip) was previously associated with idiopathic nephrotic syndrome.
Purpose of the Study:
- To investigate the role of c-mip in the pathophysiology of membranous nephropathy.
- To elucidate the mechanisms linking c-mip to podocyte dysfunction and proteinuria.
Main Methods:
- Utilized passive Heymann nephritis rat model induced by anti-megalin antibodies.
- Analyzed c-mip expression in glomeruli and podocytes.
- Assessed podocyte-related proteins (synaptopodin, death-associated protein kinase, integrin-linked kinase).
- Evaluated the effect of cyclosporine treatment on proteinuria and c-mip expression.
Main Results:
- C-mip was absent initially but overexpressed in podocytes following proteinuria induction in rats.
- Overexpression of c-mip correlated with synaptopodin downregulation and increased death-associated protein kinase and integrin-linked kinase.
- Cyclosporine treatment reduced proteinuria and c-mip levels in the rat model.
- C-mip downregulation was observed in patients with membranous nephropathy and c-mip transgenic mice.
Conclusions:
- C-mip is actively involved in podocyte injury and proteinuria in membranous nephropathy.
- C-mip overexpression contributes to podocyte dysfunction.
- Targeting c-mip may offer a therapeutic strategy for membranous nephropathy.
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