Am J Physiol Renal Physiol. 2021 Mar 1. doi: 10.1152/ajprenal.00045.2021. Online ahead of print.
RA (Retinoid acid) is synthesized mainly in the liver and has multiple functions in development, cell differentiation and proliferation, and regulation of inflammation. RA has been used to treat multiple diseases such as cancer and skin disorders. The kidney is a major organ for RA metabolism, which is altered in the diseased condition. RA is known to have renal protective effects in multiple animal models of kidney disease. RA has been shown to ameliorate podocyte injury through induction of expression of differentiation markers and regeneration of podocytes from its progenitor cells in animal models of kidney disease. The effects of RA in podocytes are mediated mainly by activation of cAMP/PKA pathway via retinoic acid receptor-α (RARα) and activation of its downstream transcription factor KLF15. Screening of RA signaling molecules in human kidney disease reveals RARRES1 as a risk gene for glomerular disease progression. RARRES1, a podocyte-specific growth arrest gene, is regulated by both high doses of RA and TNFα. Mechanistically, RARRES1 is cleaved by MMPs to generate soluble RARRES1 which then induces podocyte apoptosis through interaction with intracellular RIOK1. Therefore, a high dose of RA may induce podocyte toxicity through the upregulation of RARRES1. Based on the current findings, to avoid potential side effects we propose three strategies to develop future therapies of RA for glomerular disease: 1) develop RARα- and KLF15-specific agonists; 2) use the combination of a low dose of RARα agonist with PDE4 inhibitors; and 3) use the combination of RARα agonist with RARRES1 inhibitors.