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 2

Induction of cytoplasmic CatL protein and activity by LPS.

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Induction of cytoplasmic CatL protein and activity by LPS. (A) Cultured ...
(A) Cultured podocytes were stained using anti–LAMP-2 antibodies and the BIOMOL CV-CatL/B activity detection kit. Control cells, cells treated with 50 μg/ml of LPS for 24 hours, and cells treated with LPS and 1 μM of the selective CatL inhibitor Z-FF-FMK are shown. (B) Labeling of cultured podocytes using anti-CatL antibody, untreated or after treatment with 50 μg/ml of LPS for 24 hours. (C) Labeling of cultured podocytes using anti-CatB antibody, untreated or after treatment with 50 μg/ml of LPS for 24 hours. (D) Schematic of CatL mRNA and resulting proteins. (E) Subcellular fractionation of podocytes in isotonic sucrose prior to and 24 hours after LPS treatment. Total proteins from the soluble (S) and the particulate (P) fractions were analyzed by Western blotting.