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Reduction of Stat3 Activity Attenuates HIV-Induced Kidney Injury

Xiaobei Feng^*, Ting-Chi Lu^,, Peter Y. Chuang, Wei Fang, Krishna Ratnam, Huabao Xiong, Xinshou Ouyang, Yuhong Shen^||, David E. Levy^¶, Deborah Hyink, Mary Klotman, Vivette D'Agati^**, Ravi Iyengar, Paul E. Klotman and John C. He^,,

Department of Medicine,
Department of Pharmacology and Systems Therapeutics,
Immunobiology Center, Mount Sinai School of Medicine, New York, New York;
*Department of Nephrology, RuiJin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China;
^||Laboratory of Molecular Cell Biology, The Rockefeller University, New York, New York;
^¶Department of Pathology, New York University, New York, New York;
**Department of Pathology, Columbia University, New York, New York; and
James J. Peters VA Medical Center, Bronx, New York

Correspondence: Dr. John Cijiang He, Division of Nephrology/Department of Medicine, Box 1243, Mount Sinai School of Medicine, One Gustave L Levy Place, New York, NY 10029. Phone: 212-659-1703; Fax: 212-831-0114; E-mail: cijiang.he{at}mssm.edu

Received for publication August 21, 2008. Accepted for publication May 15, 2009.

HIV-1 Nef induces podocyte proliferation and dedifferentiation by activating the Stat3 and MAPK1,2 pathways. Activation of Stat3 also occurs in human kidneys affected by HIV-associated nephropathy (HIVAN), but its contribution to the development of HIVAN is unknown. Here, we generated HIV-1 transgenic mice (Tg26) with either 75% Stat3 activity (Tg26-SA/+) or 25% Stat3 activity (Tg26-SA/–). The kidneys of Tg26-SA/+ mice, but not Tg26-SA/– mice, showed increased Stat3 phosphorylation. The Tg26-SA/+ phenotype was not different from Tg26 mice, but Tg26-SA/– mice developed significantly less proteinuria, glomerulosclerosis, and tubulointerstitial injury. Tg26-SA/+ mice exhibited reduced expression of podocyte differentiation markers and increased expression of VEGF and proliferation markers as compared to Tg26-SA/– mice. Primary podocytes isolated from Tg26-SA/+ mice showed increased Stat3 phosphorylation and reduced expression of podocyte differentiation markers. The tubulointerstitial compartment and isolated tubules of Tg26-SA/+ mice also had increased Stat3 phosphorylation and expression of Stat3 target genes. We confirmed that the expression of the HIV-1 transgene and reduction of Stat3 activity did not affect T and B cell development. In conclusion, Stat3 plays a critical role in the pathogenesis of HIVAN.

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				L. A. Bruggeman Insight versus Quagmire with Compound HIV Transgenics J. Am. Soc. Nephrol., October 1, 2009; 20(10): 2085 - 2086. [Full Text] [PDF]

Copyright © 2009 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673