Novel retinoic acid receptor alpha agonists for treatment of kidney disease. PLoS One (2011) 6(11):e27945. doi:10.1371/journal.pone.0027945 Conflict of Interest Statement: The authors declare that the research was conducted in the absence of any commercia

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): RARa, RARb, and RARc. We have previously shown that ATRA exerts its renal protective effects mainly through the agonism of RARa. Here, we designed and synthesized a novel boron-containing derivative of the RARa-specific agonist Am580. This new derivative, BD4, binds to RARa receptor specifically and is predicted to have less toxicity based on its structure. We confirmed experimentally that BD4 binds to RARa 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 BD