title: Roflumilast enhances the renal protective effects of retinoids in an HIV-1 transgenic mouse model of rapidly progressive renal failure.
abstract: Retinoic acid decreases proteinuria and glomerulosclerosis in several animal models of kidney disease by protecting podocytes from injury. Our recent in vitro studies suggest that all-trans retinoic acid induces podocyte differentiation by activating the retinoic acid receptor-α (RARα)/cAMP/PKA/CREB pathway. When used in combination with all-trans retinoic acid, an inhibitor of phosphodiesterase 4 further enhanced podocyte differentiation by increasing intracellular cAMP. Additionally, we found that Am580, a specific RARα agonist, has similar renal protective effects as all-trans retinoic acid in a rederived colony of HIV-1 transgenic mice with rapidly progressive renal failure (HIV-Tg) that mimics human HIV-associated nephropathy. Treatment with either the inhibitor of phosphodiesterase 4, roflumilast, or Am580 significantly reduced proteinuria, attenuated kidney injury, and improved podocyte differentiation in these HIV-Tg mice. Additional renal protective effects were found when roflumilast was combined with Am580. Consistent with the in vitro data, glomeruli from HIV-Tg mice treated with both Am580 and roflumilast had more active phosphorylated CREB than with either agent alone. Thus, phosphodiesterase 4 inhibitors could be used in combination with RARα agonists to provide additional renal protection.
authors.affiliation: Department of Nephrology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
authors.forename: Yifei
authors.initials: Y
authors.lastname: Zhong
authors.forename: Yingwei
authors.initials: Y
authors.lastname: Wu
authors.forename: Ruijie
authors.initials: R
authors.lastname: Liu
authors.forename: Yueyi
authors.initials: Y
authors.lastname: Deng
authors.forename: Sandeep K
authors.initials: SK
authors.lastname: Mallipattu
authors.forename: Paul E
authors.initials: PE
authors.lastname: Klotman
authors.forename: Peter Y
authors.initials: PY
authors.lastname: Chuang
authors.forename: John C
authors.initials: JC
authors.lastname: He
mesh_terms: D016263:AIDS-Associated Nephropathy / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control* / Q000821:virology; D000631:Aminopyridines / Q000494:pharmacology*; D000818:Animals; D001549:Benzamides / Q000494:pharmacology*; D001565:Benzoates / Q000494:pharmacology*; D050882:CREB-Binding Protein / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D003521:Cyclopropanes / Q000494:pharmacology; D019610:Cytoprotection; D004195:Disease Models, Animal; D018450:Disease Progression; D004359:Drug Therapy, Combination; D005260:Female; D015658:HIV Infections / Q000150:complications / Q000188:drug therapy* / Q000235:genetics / Q000821:virology; D015497:HIV-1 / Q000235:genetics* / Q000472:pathogenicity; D007684:Kidney Tubules / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology / Q000821:virology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D058988:Phosphodiesterase 4 Inhibitors / Q000494:pharmacology*; D010766:Phosphorylation; D011507:Proteinuria / Q000517:prevention & control / Q000821:virology; D018168:Receptors, Retinoic Acid / Q000819:agonists / Q000378:metabolism; D051437:Renal Insufficiency / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control* / Q000821:virology; D000072482:Retinoic Acid Receptor alpha; D015398:Signal Transduction / Q000187:drug effects; D013764:Tetrahydronaphthalenes / Q000494:pharmacology*; D013997:Time Factors
chemical_list: D000631:Aminopyridines; D001549:Benzamides; D001565:Benzoates; D003521:Cyclopropanes; D058988:Phosphodiesterase 4 Inhibitors; C000607071:RARA protein, human; C000607072:Rara protein, mouse; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; D013764:Tetrahydronaphthalenes; C424423:Roflumilast; C068073:Am 580; D000242:Cyclic AMP; D050882:CREB-Binding Protein; C494364:Crebbp protein, mouse; D017868:Cyclic AMP-Dependent Protein Kinases