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 3

Altered dynamin staining in glomerulus after LPS treatment is CatL dependent.

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Altered dynamin staining in glomerulus after LPS treatment is CatL depen...
(A) Immunogold analysis of dynamin in podocyte FPs of rat glomerulus. Low-power view (left) depicts dynamin within the center of podocyte FPs (asterisk) as well as in electron-dense areas rich of cortical actin (a) (original magnification, ×30,000). High-power view shows gold particles, which are associated with the cytoplasmic side of vesicles (v) and with electron-dense actin areas (a) (original magnification, ×45,000). E, endosome; GBM, glomerular basement membrane; Ly, lysosome; SD, slit diaphragm; US, urinary space. (B) Immunocytochemistry of dynamin in glomeruli of WT mice before and after injection of LPS and of CatL–/– mice after injection of LPS. (C) Immunocytochemistry of samples from CatL–/– mice for glomerular dynamin and CatL. CatL–/– mice had been reconstituted with either Pre-Pro-CatL (left) or with short CatL (right) using transient gene transfer. Twenty-four hours after gene transfer, glomeruli were stained using anti-CatL and anti-dynamin hudy 1 antibody. Original magnification, ×400 (B and C). (D) Immunoblot of endogenous dynamin in cultured podocytes in response to LPS. Recombinant dynamin (REC), extracts of WT and CatL–/– podocytes, were analyzed. (E) Quantitation of dynamin in cell extracts shown in D. Dynamin signal was adjusted to actin levels.