title: Novel retinoic acid receptor alpha agonists for treatment of kidney disease.
abstract: Development of pharmacologic agents that protect podocytes from injury is a critical strategy for the treatment of kidney glomerular diseases. Retinoic acid reduces proteinuria and glomerulosclerosis in multiple animal models of kidney diseases. However, clinical studies are limited because of significant side effects of retinoic acid. Animal studies suggest that all trans retinoic acid (ATRA) attenuates proteinuria by protecting podocytes from injury. The physiological actions of ATRA are mediated by binding to all three isoforms of the nuclear retinoic acid receptors (RARs): RARα, RARβ, and RARγ. We have previously shown that ATRA exerts its renal protective effects mainly through the agonism of RARα. Here, we designed and synthesized a novel boron-containing derivative of the RARα-specific agonist Am580. This new derivative, BD4, binds to RARα receptor specifically and is predicted to have less toxicity based on its structure. We confirmed experimentally that BD4 binds to RARα with a higher affinity and exhibits less cellular toxicity than Am580 and ATRA. BD4 induces the expression of podocyte differentiation markers (synaptopodin, nephrin, and WT-1) in cultured podocytes. Finally, we confirmed that BD4 reduces proteinuria and improves kidney injury in HIV-1 transgenic mice, a model for HIV-associated nephropathy (HIVAN). Mice treated with BD4 did not develop any obvious toxicity or side effect. Our data suggest that BD4 is a novel RARα agonist, which could be used as a potential therapy for patients with kidney disease such as HIVAN.
authors: Department of Nephrology, Ruijin Hospital of Shanghai Jiantao University and Longhua Hospital of Shanghai University of Traditional Chinese Medicine, Shanghai, China.
authors: Yifei
authors: Y
authors: Zhong
authors: Yingwei
authors: Y
authors: Wu
authors: Ruijie
authors: R
authors: Liu
authors: Zhengzhe
authors: Z
authors: Li
authors: Yibang
authors: Y
authors: Chen
authors: Todd
authors: T
authors: Evans
authors: Peter
authors: P
authors: Chuang
authors: Bhaskar
authors: B
authors: Das
authors: John Cijiang
authors: JC
authors: He
mesh_terms: D016263:AIDS-Associated Nephropathy / Q000188:drug therapy; D000818:Animals; D001565:Benzoates / Q000737:chemistry / Q000494:pharmacology; D001578:Benzopyrans / Q000737:chemistry / Q000494:pharmacology*; D001667:Binding, Competitive; D001835:Body Weight / Q000187:drug effects; D001896:Boron Compounds / Q000737:chemistry / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D007674:Kidney Diseases / Q000188:drug therapy*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D008840:Microfilament Proteins / Q000235:genetics; D015394:Molecular Structure; D050199:Podocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D011507:Proteinuria / Q000517:prevention & control; D018168:Receptors, Retinoic Acid / Q000819:agonists* / Q000235:genetics; D000072482:Retinoic Acid Receptor alpha; D012176:Retinoids / Q000737:chemistry / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013764:Tetrahydronaphthalenes / Q000737:chemistry / Q000494:pharmacology; D025721:WT1 Proteins / Q000235:genetics
chemical_list: D001565:Benzoates; D001578:Benzopyrans; D001896:Boron Compounds; D008565:Membrane Proteins; D008840:Microfilament Proteins; C000607072:Rara protein, mouse; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; D012176:Retinoids; C503968:Synpo protein, mouse; D013764:Tetrahydronaphthalenes; D025721:WT1 Proteins; C113267:nephrin; C068073:Am 580