Abstract
Kidney podocytes and their slit diaphragms (SDs) form the final barrier to urinary protein loss. There is mounting evidence that SD proteins also participate in intracellular signaling pathways. The SD protein nephrin serves as a component of a signaling complex that directly links podocyte junctional integrity to actin cytoskeletal dynamics. Another SD protein, CD2-associated protein (CD2AP), is an adaptor molecule involved in podocyte homeostasis that can repress proapoptotic TGF-β signaling in podocytes. Here we show that dendrin, a protein originally identified in telencephalic dendrites, is a constituent of the SD complex, where it directly binds to nephrin and CD2AP. In experimental glomerulonephritis, dendrin relocates from the SD to the nucleus of injured podocytes. High-dose, proapoptotic TGF-β1 directly promotes the nuclear import of dendrin, and nuclear dendrin enhances both staurosporine- and TGF-β1-mediated apoptosis. In summary, our results identify dendrin as an SD protein with proapoptotic signaling properties that accumulates in the podocyte nucleus in response to glomerular injury and provides a molecular target to tackle proteinuric kidney diseases. Nuclear relocation of dendrin may provide a mechanism whereby changes in SD integrity could translate into alterations of podocyte survival under pathological conditions.
| Original language | English |
|---|---|
| Pages (from-to) | 10134-10139 |
| Number of pages | 6 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Volume | 104 |
| Issue number | 24 |
| DOIs | |
| State | Published - Jun 12 2007 |
| Externally published | Yes |
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Keywords
- Glomerular injury
- Proapoptotic signaling
- Slit diaphragm
- TGF-β signaling
ASJC Scopus subject areas
- Genetics
- General
Cite this
Nuclear relocation of the nephrin and CD2AP-binding protein dendrin promotes apoptosis of podocytes. / Asanuma, Katsuhiko; Campbell, Kirk Nicholas; Kim, Kwanghee; Faul, Christian H; Mundel, Peter.
In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 104, No. 24, 12.06.2007, p. 10134-10139.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Nuclear relocation of the nephrin and CD2AP-binding protein dendrin promotes apoptosis of podocytes
AU - Asanuma, Katsuhiko
AU - Campbell, Kirk Nicholas
AU - Kim, Kwanghee
AU - Faul, Christian H
AU - Mundel, Peter
PY - 2007/6/12
Y1 - 2007/6/12
N2 - Kidney podocytes and their slit diaphragms (SDs) form the final barrier to urinary protein loss. There is mounting evidence that SD proteins also participate in intracellular signaling pathways. The SD protein nephrin serves as a component of a signaling complex that directly links podocyte junctional integrity to actin cytoskeletal dynamics. Another SD protein, CD2-associated protein (CD2AP), is an adaptor molecule involved in podocyte homeostasis that can repress proapoptotic TGF-β signaling in podocytes. Here we show that dendrin, a protein originally identified in telencephalic dendrites, is a constituent of the SD complex, where it directly binds to nephrin and CD2AP. In experimental glomerulonephritis, dendrin relocates from the SD to the nucleus of injured podocytes. High-dose, proapoptotic TGF-β1 directly promotes the nuclear import of dendrin, and nuclear dendrin enhances both staurosporine- and TGF-β1-mediated apoptosis. In summary, our results identify dendrin as an SD protein with proapoptotic signaling properties that accumulates in the podocyte nucleus in response to glomerular injury and provides a molecular target to tackle proteinuric kidney diseases. Nuclear relocation of dendrin may provide a mechanism whereby changes in SD integrity could translate into alterations of podocyte survival under pathological conditions.
AB - Kidney podocytes and their slit diaphragms (SDs) form the final barrier to urinary protein loss. There is mounting evidence that SD proteins also participate in intracellular signaling pathways. The SD protein nephrin serves as a component of a signaling complex that directly links podocyte junctional integrity to actin cytoskeletal dynamics. Another SD protein, CD2-associated protein (CD2AP), is an adaptor molecule involved in podocyte homeostasis that can repress proapoptotic TGF-β signaling in podocytes. Here we show that dendrin, a protein originally identified in telencephalic dendrites, is a constituent of the SD complex, where it directly binds to nephrin and CD2AP. In experimental glomerulonephritis, dendrin relocates from the SD to the nucleus of injured podocytes. High-dose, proapoptotic TGF-β1 directly promotes the nuclear import of dendrin, and nuclear dendrin enhances both staurosporine- and TGF-β1-mediated apoptosis. In summary, our results identify dendrin as an SD protein with proapoptotic signaling properties that accumulates in the podocyte nucleus in response to glomerular injury and provides a molecular target to tackle proteinuric kidney diseases. Nuclear relocation of dendrin may provide a mechanism whereby changes in SD integrity could translate into alterations of podocyte survival under pathological conditions.
KW - Glomerular injury
KW - Proapoptotic signaling
KW - Slit diaphragm
KW - TGF-β signaling
UR - http://www.scopus.com/inward/record.url?scp=34547213485&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=34547213485&partnerID=8YFLogxK
U2 - 10.1073/pnas.0700917104
DO - 10.1073/pnas.0700917104
M3 - Article
VL - 104
SP - 10134
EP - 10139
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
SN - 0027-8424
IS - 24
ER -