Retinoic acid: A potential pharmacologic approach in the treatment of podocytopathy

In the setting of injury, podocytes can undergo dedifferentiation and proliferation, apoptosis, or cell detachment, resulting in proteinuria. Significant injury resulting in a loss of podocytes contributes to progressive kidney disease. Consequently, therapies that prevent podocyte injury and promote their regeneration will have a major clinical impact on glomerular disease. All-trans-retinoic acid (RA), which is a derivative of vitamin A, has many cellular functions including induction of cell differentiation, regulation of apoptosis, and inhibition of inflammation and proliferation. In addition to its established role in the treatment of variety of cancers, RA has been demonstrated to provide protection in various experimental models of kidney diseases with podocyte injury. RA produces its beneficial effects in the kidney due to its anti-inflammatory and antiproliferative effects. Also, RA helps maintain the normal morphology and preserves the differentiation markers of the podocytes. RA produces its effects in the podocytes via retinoic acid receptor-α (RAR-α). Treatment with RAR-α agonist, Am580, has a similar efficacy as RA in a mouse model of HIVAN. However, due to its systemic toxicity, clinical studies evaluating the use of RA have been challenging. Therefore, novel RAR-α agonist such as BD4 has been synthesized, which has a similar efficacy as RA and Am580, with lower toxicity.