Angiotensin II down-regulates nephrin-Akt signaling and induces podocyte injury: roleof c-Abl.
Recent studies have shown that nephrin plays a vital role in angiotensin II (Ang II)-induced podocyte injury and thus contributes to the onset of proteinuria and the progression of renal diseases, but its specific mechanism remains unclear. c-Abl is an SH2/SH3 domain-containing nonreceptor tyrosine kinase that is involved in cell survival and regulation of the cytoskeleton. Phosphorylated nephrin is able to interact with molecules containing SH2/SH3 domains, suggesting that c-Abl may be a downstream molecule of nephrin signaling. Here we report that Ang II-infused rats developed proteinuria and podocyte damage accompanied by nephrin dephosphorylation and minimal interaction between nephrin and c-Abl. In vitro, Ang II induced podocyte injury and nephrin and Akt dephosphorylation, which occurred in tandem with minimal interaction between nephrin and c-Abl. Moreover, Ang II promoted c-Abl phosphorylation and interaction between c-Abl and SH2 domain-containing 5'-inositol phosphatase 2 (SHIP2). c-Abl small interfering RNA (siRNA) and STI571 (c-Abl inhibitor) provided protection against Ang II-induced podocyte injury, suppressed the Ang II-induced c-Abl-SHIP2 interaction and SHIP2 phosphorylation, and maintained a stable level of nephrin phosphorylation. These results indicate that c-Abl is a molecular chaperone of nephrin signaling and the SHIP2-Akt pathway and that the released c-Abl contributes to Ang II-induced podocyte injury.
Division of Nephrology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, China.
Qian
Q
Yang
Division of Nephrology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, China.
Yiqiong
Y
Ma
Division of Nephrology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, China.
Yipeng
Y
Liu
Division of Nephrology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, China.
Wei
W
Liang
Division of Nephrology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, China.
Xinghua
X
Chen
Division of Nephrology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, China.
Zhilong
Z
Ren
Division of Nephrology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, China.
Huiming
H
Wang
Renal Molecular Research Laboratory, Feinstein Institute for Medical Research, Hofstra North Shore-Long Island Medical School, Great Neck, NY 11021.
Pravin C
PC
Singhal
Division of Nephrology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, China ghxding@gmail.com.
Guohua
G
Ding
D000804:Angiotensin II / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D015536:Down-Regulation / Q000187:drug effects; D055785:Gene Knockdown Techniques; D016313:Genes, abl; D000072181:Inositol Polyphosphate 5-Phosphatases; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism; D010766:Phosphorylation; D050199:Podocytes / Q000187:drug effects* / Q000378:metabolism*; D016315:Proto-Oncogene Proteins c-abl / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects; D014162:Transfection; D018909:src Homology Domains
D008565:Membrane Proteins; D034741:RNA, Small Interfering; C113267:nephrin; D000804:Angiotensin II; D016315:Proto-Oncogene Proteins c-abl; D051057:Proto-Oncogene Proteins c-akt; D010744:Phosphoric Monoester Hydrolases; D000072181:Inositol Polyphosphate 5-Phosphatases; C000606435:Inppl1 protein, mouse; C000606436:Inppl1 protein, rat; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases