title: 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.
authors.affiliation: INSERM, U 955, Equipe 21, Créteil, France.
authors.forename: Kelhia
authors.initials: K
authors.lastname: Sendeyo
authors.forename: Vincent
authors.initials: V
authors.lastname: Audard
authors.forename: Shao-yu
authors.initials: SY
authors.lastname: Zhang
authors.forename: Qingfeng
authors.initials: Q
authors.lastname: Fan
authors.forename: Khedidja
authors.initials: K
authors.lastname: Bouachi
authors.forename: Mario
authors.initials: M
authors.lastname: Ollero
authors.forename: Catherine
authors.initials: C
authors.lastname: Rucker-Martin
authors.forename: Elodie
authors.initials: E
authors.lastname: Gouadon
authors.forename: Dominique
authors.initials: D
authors.lastname: Desvaux
authors.forename: Franck
authors.initials: F
authors.lastname: Bridoux
authors.forename: Georges
authors.initials: G
authors.lastname: Guellaën
authors.forename: Pierre
authors.initials: P
authors.lastname: Ronco
authors.forename: Philippe
authors.initials: P
authors.lastname: Lang
authors.forename: Andre
authors.initials: A
authors.lastname: Pawlak
authors.forename: Djillali
authors.initials: D
authors.lastname: Sahali
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000328:Adult; D051017:Apoptosis Regulatory Proteins / Q000502:physiology; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000502:physiology; D002352:Carrier Proteins / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D016572:Cyclosporine / Q000627:therapeutic use; D064550:Death-Associated Protein Kinases; D015433:Glomerulonephritis, Membranous / Q000188:drug therapy / Q000473:pathology*; D006801:Humans; D050199:Podocytes / Q000473:pathology / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000502:physiology; D015854:Up-Regulation; D000099200:Scaffold Protein ILK
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D002352:Carrier Proteins; D016572:Cyclosporine; D064550:Death-Associated Protein Kinases; D017346:Protein Serine-Threonine Kinases; D000099200:Scaffold Protein ILK; C540426:CMIP protein, human