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.
Highlights
Glomerular kidney disease is a major cause of End-Stage-RenalDisease (ESRD) in the United States [1]
We found that Am580, a retinoic acid receptor-a (RARa)-specific agonist, induces podocyte differentiation in vitro and attenuates kidney injury of Tg26 mice in vivo [23]
We found that BD4 significantly stimulates the expression of synaptopodin, nephrin and Wilm’s Tumor 1 (WT1) to levels similar what has been previously observed with all trans retinoic acid (ATRA) or Am480 at the same concentration (1 mM) (Figure 5A)
Summary
Glomerular kidney disease is a major cause of End-Stage-RenalDisease (ESRD) in the United States [1]. Treatment options for these diseases are scarce. Steroids and immunosuppressive medications are first-line treatments for glomerular diseases. Resistant cases are frequently observed and side effects from the treatment are multiple. Treatment of glomerular diseases with angiotensin converting enzyme inhibitors or angiotensin receptor blockers reduces proteinuria and slows the progression of kidney disease. It is important to identify new treatment targets or regimes
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