title: Role of the retinoic acid receptor-α in HIV-associated nephropathy.
abstract: All-trans retinoic acid protects against the development of HIV-associated nephropathy (HIVAN) in HIV-1 transgenic mice (Tg26). In vitro, all-trans retinoic acid inhibits HIV-induced podocyte proliferation and restores podocyte differentiation markers by activating its receptor-α (RARα). Here, we report that Am580, a water-soluble RARα-specific agonist, attenuated proteinuria, glomerosclerosis, and podocyte proliferation, and restored podocyte differentiation markers in kidneys of Tg26 mice. Furthermore, RARα-/- Tg26 mice developed more severe kidney and podocyte injury than did RARα+/- Tg26 mice. Am580 failed to ameliorate kidney injury in RARα-/- Tg26 mice, confirming our hypothesis that Am580 acts through RARα. Although the expression of RARα-target genes was suppressed in the kidneys of Tg26 mice and of patients with HIVAN, the expression of RARα in the kidney was not different between patients with HIVAN and minimal change disease. However, the tissue levels of retinoic acid were reduced in the kidney cortex and isolated glomeruli of Tg26 mice. Consistent with this, the expression of two key enzymes in the retinoic acid synthetic pathway, retinol dehydrogenase type 1 and 9, and the overall enzymatic activity for retinoic acid synthesis were significantly reduced in the glomeruli of Tg26 mice. Thus, a defect in the endogenous synthesis of retinoic acid contributes to loss of the protection by retinoic acid in HIVAN. Hence, RARα agonists may be potential agents for the treatment of HIVAN.
authors.affiliation: Division of Nephrology, Mount Sinai School of Medicine, New York, New York, USA.
authors.forename: Krishna K
authors.initials: KK
authors.lastname: Ratnam
authors.affiliation: RuiJin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Xiaobei
authors.initials: X
authors.lastname: Feng
authors.affiliation: Division of Nephrology, Mount Sinai School of Medicine, New York, New York, USA.
authors.forename: Peter Y
authors.initials: PY
authors.lastname: Chuang
authors.affiliation: Division of Nephrology, Mount Sinai School of Medicine, New York, New York, USA.
authors.forename: Vikram
authors.initials: V
authors.lastname: Verma
authors.affiliation: Division of Nephrology, Mount Sinai School of Medicine, New York, New York, USA.
authors.forename: Ting-Chi
authors.initials: TC
authors.lastname: Lu
authors.affiliation: Department of Nutritional Science and Toxicology, University of California, Berkeley, Berkeley, California, USA.
authors.forename: Jinshan
authors.initials: J
authors.lastname: Wang
authors.affiliation: RuiJin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Yuanmeng
authors.initials: Y
authors.lastname: Jin
authors.affiliation: Division of Hematology, Department of Medicine, Mount Sinai School of Medicine, New York, New York, USA.
authors.forename: Eduardo F
authors.initials: EF
authors.lastname: Farias
authors.affiliation: Department of Nutritional Science and Toxicology, University of California, Berkeley, Berkeley, California, USA.
authors.forename: Joseph L
authors.initials: JL
authors.lastname: Napoli
authors.affiliation: RuiJin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Nan
authors.initials: N
authors.lastname: Chen
authors.affiliation: Division of Nephrology, Mount Sinai School of Medicine, New York, New York, USA.
authors.forename: Lewis
authors.initials: L
authors.lastname: Kaufman
authors.affiliation: Division of Nephrology, McGill University Health Centre, Montreal, Quebec, Canada.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Takano
authors.affiliation: Department of Pathology, Columbia University, New York, New York, USA.
authors.forename: Vivette D
authors.initials: VD
authors.lastname: D'Agati
authors.affiliation: Division of Nephrology, Mount Sinai School of Medicine, New York, New York, USA.
authors.forename: Paul E
authors.initials: PE
authors.lastname: Klotman
authors.affiliation: Division of Nephrology, Mount Sinai School of Medicine, New York, New York, USA; Department of Pharmacology and Systems Therapeutics, Mount Sinai School of Medicine, New York, New York, USA; James J. Peters VA Medical Center, New York, New York, USA. Electronic address: cijiang.he@mssm.edu.
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; D000429:Alcohol Oxidoreductases / Q000378:metabolism; D000818:Animals; D001565:Benzoates / Q000494:pharmacology; D002454:Cell Differentiation; D049109:Cell Proliferation; D004195:Disease Models, Animal; D005260:Female; D005921:Glomerulonephritis / Q000378:metabolism / Q000517:prevention & control / Q000821:virology; D015497:HIV-1 / Q000235:genetics*; D006801:Humans; D006913:Hydroxysteroid Dehydrogenases / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D050199:Podocytes / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D011507:Proteinuria / Q000378:metabolism / Q000517:prevention & control / Q000821:virology; D018168:Receptors, Retinoic Acid / Q000819:agonists / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000072482:Retinoic Acid Receptor alpha; D012176:Retinoids / Q000378:metabolism; D012720:Severity of Illness Index; D015398:Signal Transduction / Q000187:drug effects; D013764:Tetrahydronaphthalenes / Q000494:pharmacology; D013997:Time Factors
chemical_list: D001565:Benzoates; C000607071:RARA protein, human; C000607072:Rara protein, mouse; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; D012176:Retinoids; D013764:Tetrahydronaphthalenes; C082925:retinoic acid receptor beta; C068073:Am 580; D000429:Alcohol Oxidoreductases; D006913:Hydroxysteroid Dehydrogenases; C441646:Rdh1 protein, mouse; C109795:cis-retinol - androgen dehydrogenase