Proteinuria: an enzymatic disease of the podocyte?
Proteinuria is a major health-care problem that affects several hundred million people worldwide. Proteinuria is a cardinal sign and a prognostic marker of kidney disease, and also an independent risk factor for cardiovascular morbidity and mortality. Microalbuminuria is the earliest cue of renal complications of diabetes, obesity, and the metabolic syndrome. It can often progress to overt proteinuria that in 10-50% of patients is associated with the development of chronic kidney disease, ultimately requiring dialysis or transplantation. Therefore, reduction or prevention of proteinuria is highly desirable. Here we review recent novel insights into the pathogenesis and treatment of proteinuria, with a special emphasis on the emerging concept that proteinuria can result from enzymatic cleavage of essential regulators of podocyte actin dynamics by cytosolic cathepsin L (CatL), resulting in a motile podocyte phenotype. Finally, we describe signaling pathways controlling the podocyte actin cytoskeleton and motility and how these pathways can be manipulated for therapeutic benefit.
Mundel
Peter
P
Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida 33136, USA. pmundel@med.miami.edu
Reiser
Jochen
J
D000199:Actins / Q000378:metabolism*; D000818:Animals; D018122:B7-1 Antigen / Q000378:metabolism; D056668:Cathepsin L / Q000378:metabolism*; D016572:Cyclosporine / Q000494:pharmacology / Q000627:therapeutic use; D003600:Cytosol / Q000201:enzymology; D006801:Humans; D008840:Microfilament Proteins / Q000378:metabolism; D050199:Podocytes / Q000187:drug effects / Q000201:enzymology*; D011507:Proteinuria / Q000201:enzymology* / Q000209:etiology / Q000628:therapy; D015398:Signal Transduction; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism; D020830:rac1 GTP-Binding Protein / Q000378:metabolism
D000199:Actins; D018122:B7-1 Antigen; D008840:Microfilament Proteins; C503967:SYNPO protein, human; D016572:Cyclosporine; D056668:Cathepsin L; D020764:cdc42 GTP-Binding Protein; D020830:rac1 GTP-Binding Protein