title: Cathepsin L is crucial for the development of early experimental diabetic nephropathy.
abstract: Proteinuria is one of the first clinical signs of diabetic nephropathy and an independent predictor for the progression to renal failure. Cathepsin L, a lysosomal cysteine protease, can be involved in the development of proteinuria by degradation of proteins that are important for normal podocyte architecture, such as the CD2-associated protein, synaptopodin, and dynamin. Cathepsin L also activates heparanase, a heparan sulfate endoglycosidase previously shown to be crucial for the development of diabetic nephropathy. Here, we evaluated the exact mode of action of cathepsin L in the development of proteinuria in streptozotocin-induced diabetes. Cathepsin L-deficient mice, in contrast to their wild-type littermates, failed to develop albuminuria, mesangial matrix expansion, tubulointerstitial fibrosis, and renal macrophage influx and showed a normal renal function. In wild-type mice the early development of albuminuria correlated with the activation of heparanase and loss of heparan sulfate expression, whereas loss of synaptopodin expression and podocyte damage occurred at a later stage. Thus, cathepsin L is causally involved in the pathogenesis of experimental diabetic nephropathy. Most likely, cathepsin L-dependent heparanase activation is crucial for the development of albuminuria and renal damage.
authors: Department of Nephrology, Radboud University Medical Center, Nijmegen, the Netherlands.
authors: Marjolein
authors: M
authors: Garsen
authors: Department of Nephrology, Radboud University Medical Center, Nijmegen, the Netherlands.
authors: Angelique L W M M
authors: AL
authors: Rops
authors: Department of Pathology, Radboud University Medical Center, Nijmegen, the Netherlands.
authors: Henry
authors: H
authors: Dijkman
authors: Department of Pathology, Radboud University Medical Center, Nijmegen, the Netherlands.
authors: Brigith
authors: B
authors: Willemsen
authors: Department of Matrix Biochemistry, Radboud University Medical Center, Nijmegen, the Netherlands.
authors: Toin H
authors: TH
authors: van Kuppevelt
authors: Department of Pharmacology and Toxicology, Radboud University Medical Center, Nijmegen, the Netherlands.
authors: Frans G
authors: FG
authors: Russel
authors: Department of Nephrology, Einthoven Laboratory for Vascular Medicine, Leiden University Medical Center, Leiden, the Netherlands.
authors: Ton J
authors: TJ
authors: Rabelink
authors: Department of Nephrology, Radboud University Medical Center, Nijmegen, the Netherlands.
authors: Jo H M
authors: JH
authors: Berden
authors: Institute of Molecular Medicine and Cell Research and BIOSS Centre for Biological Signaling Studies, Albert-Ludwigs-University, Freiburg, Germany.
authors: Thomas
authors: T
authors: Reinheckel
authors: Department of Nephrology, Radboud University Medical Center, Nijmegen, the Netherlands. Electronic address: Johan.vanderVlag@radboudumc.nl.
authors: Johan
authors: J
authors: van der Vlag
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D056668:Cathepsin L / Q000378:metabolism*; D003598:Cytoskeletal Proteins / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000150:complications*; D003928:Diabetic Nephropathies / Q000209:etiology*; D034281:Dynamins / Q000378:metabolism; D005966:Glucuronidase / Q000378:metabolism; D008810:Mice, Inbred C57BL; D008840:Microfilament Proteins / Q000378:metabolism; D000099175:Heparanase
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D056668:Cathepsin L; D003598:Cytoskeletal Proteins; D034281:Dynamins; D005966:Glucuronidase; D008840:Microfilament Proteins; D000099175:Heparanase; C114545:CD2-associated protein; C503968:Synpo protein, mouse
keywords: diabetic nephropathy; glomerulus; proteinuria