title: Retinoic acid inhibits HIV-1-induced podocyte proliferation through the cAMP pathway.
abstract: 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.
authors.affiliation: Department of Medicine, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, NY 10029, USA. cijiang.he@mssm.edu
authors.forename: John Cijiang
authors.initials: JC
authors.lastname: He
authors.forename: Ting-Chi
authors.initials: TC
authors.lastname: Lu
authors.forename: Margaret
authors.initials: M
authors.lastname: Fleet
authors.forename: Masaaki
authors.initials: M
authors.lastname: Sunamoto
authors.forename: Mohammad
authors.initials: M
authors.lastname: Husain
authors.forename: Wei
authors.initials: W
authors.lastname: Fang
authors.forename: Susana
authors.initials: S
authors.lastname: Neves
authors.forename: Yibang
authors.initials: Y
authors.lastname: Chen
authors.forename: Stuart
authors.initials: S
authors.lastname: Shankland
authors.forename: Ravi
authors.initials: R
authors.lastname: Iyengar
authors.forename: Paul E
authors.initials: PE
authors.lastname: Klotman
mesh_terms: D016263:AIDS-Associated Nephropathy / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D015658:HIV Infections / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D015497:HIV-1 / Q000472:pathogenicity*; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D010641:Phenotype; D010766:Phosphorylation; D050199:Podocytes / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D018168:Receptors, Retinoic Acid / Q000378:metabolism; D000072482:Retinoic Acid Receptor alpha; D050796:STAT3 Transcription Factor / Q000378:metabolism; D014212:Tretinoin / Q000494:pharmacology*
chemical_list: C000607071:RARA protein, human; C000607072:Rara protein, mouse; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D014212:Tretinoin; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D048049:Extracellular Signal-Regulated MAP Kinases