Objective: HIV-1 gene expression in kidney epithelial cells is thought to be responsible for the pathogenesis of HIV-1-associated nephropathy (HIVAN). Signal transducer and activator of transcription (STAT) 3 signaling is activated in podocytes of patients with HIVAN and drives the dedifferentiation and proliferation of podocytes in culture. We confirm here that deletion of podocyte STAT3 is sufficient to mitigate the glomerular as well as tubulointerstitial findings of HIVAN.
Methods: To demonstrate the functional role of podocyte STAT3 in the pathogenesis of HIVAN we compared the development of HIVAN in Tg26 HIV-transgenic mice with and without deletion of STAT3 in the podocyte.
Results: Tg26 mice with podocyte-specific STAT3 deletion developed significantly less weight loss, albuminuria, and renal function impairment compared to Tg26 mice without STAT3 deletion. Tg26 mice with podocyte STAT3 deletion also had significantly less glomerular collapse, sclerosis, epithelial cell hyperplasia, podocyte dedifferentiation, and proinflammatory STAT3 target gene expression; and tubulointerstitial changes of HIVAN, including tubular atrophy, degeneration, apoptosis, and lymphocyte infiltration, were also significantly reduced compared to Tg26 mice without STAT3 deletion.
Conclusion: Development of glomerular as well as tubulointerstitial injuries in the Tg26 HIVAN model is dependent on podocyte STAT3 expression. Inhibition of STAT3 could be a potential adjunctive therapy for the treatment of HIVAN.
aDivision of Nephrology, Mount Sinai School of Medicine, New York, New York, USA
bRenal Division and Molecular Cell Laboratory for Kidney Disease, Renji Hospital, Shanghai Jiaotong University School of Medicine
cDivision of Nephrology, Shanghai First People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
dBaylor College of Medicine, Houston, Texas
eRenal Section, James J Peter Veterans Affairs Medical Center, Bronx, New York, USA.
*Leyi Gu and Yan Dai contributed equally to the writing of this article.
Correspondence to Peter Y. Chuang, Division of Nephrology, Department of Medicine, Mount Sinai School of Medicine, One Gustave L Levy Place, Box 1243, New York, NY 10029, USA. Tel: +1 212 659 1752; fax: +1 212 831 0114; e-mail: firstname.lastname@example.org
Received 23 August, 2012
Revised 21 December, 2012
Accepted 17 January, 2013