Proteolytic processing of dynamin by cytoplasmic cathepsin L is a mechanism for proteinuric kidney disease
Sanja Sever, … , Boris Nikolic, Jochen Reiser
Sanja Sever, … , Boris Nikolic, Jochen Reiser
Published August 1, 2007
Citation Information: J Clin Invest. 2007;117(8):2095-2104. https://doi.org/10.1172/JCI32022.
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Research Article

Proteolytic processing of dynamin by cytoplasmic cathepsin L is a mechanism for proteinuric kidney disease

Abstract

Kidney podocytes and their foot processes maintain the ultrafiltration barrier and prevent urinary protein loss (proteinuria). Here we show that the GTPase dynamin is essential for podocyte function. During proteinuric kidney disease, induction of cytoplasmic cathepsin L leads to cleavage of dynamin at an evolutionary conserved site, resulting in reorganization of the podocyte actin cytoskeleton and proteinuria. Dynamin mutants that lack the cathepsin L site, or render the cathepsin L site inaccessible through dynamin self-assembly, are resistant to cathepsin L cleavage. When delivered into mice, these mutants restored podocyte function and resolve proteinuria. Our study identifies dynamin as a critical regulator of renal permselectivity that is specifically targeted by proteolysis under pathological conditions.

Authors

Sanja Sever, Mehmet M. Altintas, Sharif R. Nankoe, Clemens C. Möller, David Ko, Changli Wei, Joel Henderson, Elizabetta C. del Re, Lianne Hsing, Ann Erickson, Clemens D. Cohen, Matthias Kretzler, Dontscho Kerjaschki, Alexander Rudensky, Boris Nikolic, Jochen Reiser

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Figure 1

CatL is essential for proteinuric kidney diseases.

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CatL is essential for proteinuric kidney diseases. (A) Quantitative rt-P...
(A) Quantitative rt-PCR of microdissected glomeruli from human biopsies of patients with acquired proteinuric diseases: minimal change disease (MCD; n = 7), membranous glomerulonephritis (MGN; n = 9), focal segmental glomerulosclerosis (FSGS; n = 7), and diabetic nephropathy (DN; n = 10). **P < 0.01. CON, control (n = 8). (B) CatL labeling of normal human kidney. (C) CatL labeling of human kidney with diabetic nephropathy, mildly reduced renal function, and nephrotic range proteinuria. (D) Immunocytochemistry of mouse glomeruli using monoclonal anti-CatL antibody. WT mice received either PBS (WT CON) or LPS (WT LPS). LPS was also injected into CatL–/– mice (CatL–/– LPS). Original magnification, ×400 (C and D). (E) Electron micrographs of FPs. (F) Urinary protein levels determined using the standard Bradford protein assay. Urine was collected immediately before (Baseline) and 48 hours after addition of LPS. Each bar represents at least 8 animals.