CD2AP in mouse and human podocytes controls a proteolytic program that regulates cytoskeletal structure and cellular survival
Suma Yaddanapudi, … , Sanja Sever, Jochen Reiser
Suma Yaddanapudi, … , Sanja Sever, Jochen Reiser
Published October 3, 2011; First published September 12, 2011
Citation Information: J Clin Invest. 2011;121(10):3965-3980. https://doi.org/10.1172/JCI58552.
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Categories: Research Article Nephrology

CD2AP in mouse and human podocytes controls a proteolytic program that regulates cytoskeletal structure and cellular survival

Abstract

Kidney podocytes are highly differentiated epithelial cells that form interdigitating foot processes with bridging slit diaphragms (SDs) that regulate renal ultrafiltration. Podocyte injury results in proteinuric kidney disease, and genetic deletion of SD-associated CD2-associated protein (CD2AP) leads to progressive renal failure in mice and humans. Here, we have shown that CD2AP regulates the TGF-β1–dependent translocation of dendrin from the SD to the nucleus. Nuclear dendrin acted as a transcription factor to promote expression of cytosolic cathepsin L (CatL). CatL proteolyzed the regulatory GTPase dynamin and the actin-associated adapter synaptopodin, leading to a reorganization of the podocyte microfilament system and consequent proteinuria. CD2AP itself was proteolyzed by CatL, promoting sustained expression of the protease during podocyte injury, and in turn increasing the apoptotic susceptibility of podocytes to TGF-β1. Our study identifies CD2AP as the gatekeeper of the podocyte TGF-β response through its regulation of CatL expression and defines a molecular mechanism underlying proteinuric kidney disease.

Authors

Suma Yaddanapudi, Mehmet M. Altintas, Andreas D. Kistler, Isabel Fernandez, Clemens C. Möller, Changli Wei, Vasil Peev, Jan B. Flesche, Anna-Lena Forst, Jing Li, Jaakko Patrakka, Zhijie Xiao, Florian Grahammer, Mario Schiffer, Tobias Lohmüller, Thomas Reinheckel, Changkyu Gu, Tobias B. Huber, Wenjun Ju, Markus Bitzer, Maria P. Rastaldi, Phillip Ruiz, Karl Tryggvason, Andrey S. Shaw, Christian Faul, Sanja Sever, Jochen Reiser

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Figure 1

High level of TGF-β1 induces expression of CatL.

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High level of TGF-β1 induces expression of CatL. (A) Levels of Tgfb1, Ct...
(A) Levels of Tgfb1, Ctsl, and control gene in glomeruli of TGF-β1 Tg and WT animals. Phenotype categorization is as described previously (23). (B) H&E-stained sections of the renal cortex, showing increased CatL staining in TGF-β1 Tg mice. Kidneys of WT and TGF-β1 Tg mice were stained for CatL using anti–cytosolic CatL antibody, and nuclei were stained using DAPI. (C) CatL staining levels in sections from B. ***P < 0.001. (D) H&E-stained sections showing dendrin localization in the nucleus of the podocytes in TGF-β1 Tg animals (arrows). Kidneys of WT and TGF-β1 mice were stained for dendrin using anti-dendrin antibody. (E) Dendrin staining levels in sections from D. ***P < 0.001. (F and G) H&E-stained sections showing increased CatL staining in glomerulus of 3-week-old Cd2ap–/– mice (arrows). Kidneys of WT and Cd2ap–/– mice were stained for CatL using anti–cytosolic CatL antibody, and nuclei were stained using DAPI. (H) Dendrin localization in glomerulus of WT and Cd2ap–/– mice at different stages of development. WT1 was used to stain podocyte nuclei (red). In the young glomerulus, dendrin (green) was localized at the membrane (ribbon staining pattern), without any colocalization with WT1. At 4 weeks, dendrin staining was still localized to the plasma membrane in WT mice, but was predominantly found in the nucleus costaining with WT1 in Cd2ap–/– mice. Scale bars: 20 μm (B, D, F, and G); 30 μm (H).