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HIV-1 Upregulates VEGF in Podocytes

Sonal Navin Korgaonkar^*, Xiaobei Feng, Michael D. Ross^*, Ting-chi Lu^*,, Vivette D'Agati, Ravi Iyengar^||, Paul E. Klotman^* and John Cijiang He^*,

Departments of ^* Medicine and ^|| Pharmacology and Systems Therapeutics, Mount Sinai School of Medicine, New York, James J Peters VA Medical Center, Bronx, Department of Pathology, Columbia University, New York, New York; and Department of Nephrology, Ruijin Hospital, Shanghai, China

Correspondence: Dr. John Cijiang He, 1 Gustave Levy Place, New York, NY 10029. Phone: 212-241-4060; Fax: 212-987-0389; E-mail: cijiang.he{at}mssm.edu

Received for publication May 31, 2007. Accepted for publication February 27, 2008.

HIV-associated nephropathy (HIVAN) is characterized by collapsing FSGS. Because transgenic mice with podocyte-specific overexpression of the vascular endothelial growth factor 164 (VEGF₁₆₄) isoform also develop collapsing FSGS, we sought to determine whether VEGF plays a role in HIVAN. Compared with controls, immunohistochemistry revealed that kidneys from HIV-1–transgenic mice (Tg26) and from patients with HIVAN had greater expression of both VEGF and its transcriptional regulator, hypoxia-inducible factor 2 (HIF-2). Similarly, mRNA and protein levels of VEGF and HIF-2 were increased in HIV-infected podocytes in vitro, and this transcriptional upregulation was found to be stimulated by the HIV viral protein Nef in a Src kinase–and Stat3-dependent manner. HIV-1 also upregulated VEGFR2 and its co-receptor neuropilin-1 and suppressed the expression of semaphorin 3a in the podocyte. Exogenous VEGF stimulated proliferation and de-differentiation of podocytes, which are features of collapsing FSGS, and VEGFR2 neutralizing antibodies reversed these features in podocytes infected with HIV-1 or isolated from Tg26 mice. In conclusion, HIV-1 induces VEGF and VEGFR2 expression in podocytes, and this may be a critical step in the pathogenesis of HIVAN.

Copyright © 2008 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673