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Retinoic Acid Inhibits HIV-1–Induced Podocyte Proliferation through the cAMP Pathway

John Cijiang He^*,,, Ting-Chi Lu^*, Margaret Fleet, Masaaki Sunamoto^*, Mohammad Husain^*, Wei Fang^*, Susana Neves, Yibang Chen, Stuart Shankland, Ravi Iyengar and Paul E. Klotman^*

Departments of ^* Medicine and Pharmacology and Biochemistry, Mount Sinai School of Medicine, New York, and Nephrology/Medicine, James J. Peters VA Medical Center, Bronx, New York; and Department of Medicine, University of Washington, Seattle, Washington

Address correspondence to: Dr. John Cijiang He, Box 1243, Division of Nephrology, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, NY 10029. Phone: 212-241-8004; Fax: 212-987-0389; E-mail: cijiang.he{at}mssm.edu

Received for publication July 12, 2006. Accepted for publication October 23, 2006.

HIV-associated nephropathy is characterized by renal podocyte proliferation and dedifferentiation. This study found that all-trans retinoic acid (atRA) reverses the effects of HIV-1 infection in podocytes. Treatment with atRA reduced cell proliferation rate by causing G1 arrest and restored the expression of the differentiation markers (synaptopodin, nephrin, podocin, and WT-1) in HIV-1–infected podocytes. It is interesting that both atRA and 9-cis RA increased intracellular cAMP levels in podocytes. Podocytes expressed most isoforms of retinoic acid receptors (RAR) and retinoid X receptors (RXR) with the exception of RXR. RAR antagonists blocked atRA-induced cAMP production and its antiproliferative and prodifferentiation effects on podocytes, suggesting that RAR is required. For determination of the effect of increased intracellular cAMP on HIV-infected podocytes, cells were stimulated with either forskolin or 8-bromo-cAMP. Both compounds inhibited cell proliferation significantly and restored synaptopodin expression in HIV-infected podocytes. The effects of atRA were abolished by Rp-cAMP, an inhibitor of the cAMP/protein kinase A pathway and were enhanced by rolipram, an inhibitor of phosphodiesterase 4, suggesting that the antiproliferative and prodifferentiation effects of atRA on HIV-infected podocytes are cAMP dependent. Furthermore, both atRA and forskolin suppressed HIV-induced mitogen-activated protein kinase 1 and 2 and Stat3 phosphorylation. In vivo, atRA reduced proteinuria, cell proliferation, and glomerulosclerosis in HIV-1–transgenic mice. These findings suggest that atRA reverses the abnormal phenotype in HIV-1–infected podocytes by stimulating RAR-mediated intracellular cAMP production. These results demonstrate the mechanism by which atRA reverses the proliferation of podocytes that is induced by HIV-1.

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