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, Paul E Klotman

Department of Medicine, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, NY 10029, USA. cijiang.he@mssm.edu

Journal of the American Society of Nephrology : JASN 2007 Jan

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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 RXRgamma. RARalpha antagonists blocked atRA-induced cAMP production and its antiproliferative and prodifferentiation effects on podocytes, suggesting that RARalpha 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 RARalpha-mediated intracellular cAMP production. These results demonstrate the mechanism by which atRA reverses the proliferation of podocytes that is induced by HIV-1.

Citation

John Cijiang He, Ting-Chi Lu, Margaret Fleet, Masaaki Sunamoto, Mohammad Husain, Wei Fang, Susana Neves, Yibang Chen, Stuart Shankland, Ravi Iyengar, Paul E Klotman. Retinoic acid inhibits HIV-1-induced podocyte proliferation through the cAMP pathway. Journal of the American Society of Nephrology : JASN. 2007 Jan;18(1):93-102