Disparate roles of retinoid acid signaling molecules in kidney disease

Anqun Chen, Yu Liu, Yu Lu, Kyung Lee, John Cijiang He

Research output: Contribution to journalReview articlepeer-review

21 Scopus citations

Abstract

Retinoid acid (RA) 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 the cAMP/PKA pathway via RA receptor-a (RARa) and activation of its downstream transcription factor, Kruppel-like factor 15. Screening of RA signaling molecules in human kidney disease has revealed RAR responder protein 1 (RARRES1) as a risk gene for glomerular disease progression. RARRES1, a podocyte-specific growth arrest gene, is regulated by high doses of both RA and TNFa. Mechanistically, RARRES1 is cleaved by matrix metalloproteinases to generate soluble RARRES1, which then induces podocyte apoptosis through interaction with intracellular RIO kinase 1. Therefore, a high dose of RA may induce podocyte toxicity through 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 RARa- and Kruppel-like factor 15-specific agonists, 2) use the combination of a low dose of RAR-a agonist with phosphodiesterase 4 inhibitors, and 3) use a combination of RARa agonist with RARRES1 inhibitors.

Original languageEnglish
Pages (from-to)F683-F692
JournalAmerican Journal of Physiology - Renal Physiology
Volume320
Issue number5
DOIs
StatePublished - May 2021

Keywords

  • Glomerular disease
  • Podocytes
  • Retinoic acid
  • Retinoic acid receptor responder protein 1
  • Retinoic acid receptors

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