Disparate roles of retinoid acid signaling molecules in kidney disease

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-α (RARα) 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 TNF-α. 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 RARα- and Kruppel-like factor 15-specific agonists, 2) use the combination of a low dose of RAR-α agonist with phosphodiesterase 4 inhibitors, and 3) use a combination of RARα agonist with RARRES1 inhibitors.NEW & NOTEWORTHY Retinoic acid (RA) exerts pleotropic cellular effects, including induction of cell differentiation while inhibiting proliferation and inflammation. These effects are mediated by both RA responsive element-dependent or -independent pathways. In kidneys, RA confers renoprotection by signaling through podocyte RA receptor (RAR)α and activation of cAMP/PKA/Kruppel-like factor 15 pathway to promote podocyte differentiation. Nevertheless, in kidney disease settings, RA can also promote podocyte apoptosis and loss through downstream expression of RAR responder protein 1, a recently described risk factor for glomerular disease progression. These disparate roles of RA underscore the complexity of its effects in kidney homeostasis and disease, and a need to target specific RA-mediated pathways for effective therapeutic treatments against kidney disease progression.

Keywords: glomerular disease; podocytes; retinoic acid; retinoic acid receptor responder protein 1; retinoic acid receptors.

Graphical abstract

Figure 1.

Retinoic acid (RA) metabolism and signaling. A: vitamin A obtained from diet is metabolized into β-carotene, which is absorbed by intestinal epithelial cells and esterified into retinyl esters by the enzyme lecithin retinol acyltransferase (LRAT). B: retinyl esters are carried together with chylomicrons in the bloodstream; they are then captured by hepatocytes and hydrolyzed into retinol. C: retinol binds to retinol-binding protein (RBP) in the bloodstream and transported into the cytosol via the stimulated by retinoic acid 6 (STRA6) receptor. D: in the cytosol, RA is generated from retinol by two sequential reactions. Retinol is first oxidized into retinal by alcohol dehydrogenase (ADH) and then retinal is oxidized by the enzyme retinal dehydrogenase (RALDH) to generate RA. E: the function of RA depends on the type of RBP that RA binds. If the fatty acid-binding protein 5 (FABP5)/cellular retinol-binding protein II (CRABPII) ratio is low, RA binds mostly to CRABPII, which delivers it to the retinoic acid receptor (RAR)/retinoid X receptor (RXR) complex to regulate the transcription of target genes (proapoptotic genes) by binding to retinoic acid-responsive element (RAREs). When the FABP5-to-CRABPII ratio is high, all-trans-retinoic acid (ATRA) binds mostly to FABP5, which targets RA to other receptors, such as peroxisome proliferator-activated receptor-β/δ, activating mostly survival genes. F: the retinol-RBP4 complex is filtered by the kidneys and is reabsorbed in proximal tubule cells by the megalin-mediated pathway. CYP, cytochrome P-450. PPAR, peroxisome proliferator-activated receptor.

Figure 2.

Cellular and molecular mechanisms of retinoic acid (RA) in podocytes. The protective effects of RA on podocytes depend on the types of injury. RA can inhibit podocyte proliferation and differentiation in mice with human immunodeficiency virus (HIV)-associated nephropathy (HIVAN) through activation of the cAMP/PKA pathway and upregulation of Wilms’ tumor-1 (WT-1) and Kruppel-like factor 15 (KLF15) expression. In mice with crescentic glomerulonephritis [nephrotoxic serum (NTS) nephritis] and focal segmental glomerulosclerosis (FSGS), RA stimulates podocyte regeneration from parietal epithelial cells (PECs) via activation of retinoic acid receptor (RAR)α, and this protective effect is impaired by albuminuria. However, a high dose of RA may induce retinoic acid receptor responder protein 1 (RARRES1) expression, which can cause podocyte apoptosis, a potential side effect of RA. ADR, adriamycin; DKD, diabetic kidney disease.

Figure 3.

Summary of the mechanism by which retinoic acid receptor responder protein 1 (RARRES1) regulates podocyte apoptosis. In the diseased kidneys, inflammation, such as through TNF-α, induces expression of RARRES1, which is cleaved into its soluble form, probably mediated by inflammation-stimulated matrix metalloproteinases (MMPs). Soluble RARRES1 is then endocytosed and interacts with intracellular RIO kinase 1 (RIOK1), leading to the inactivation of RIOK1, thereby increasing p53 phosphorylation and podocyte apoptosis. Podocyte loss promotes the progression of kidney disease. CKD, chronic kidney disease.

Figure 4.

Therapeutic strategy of retinoic acid (RA) in kidney disease for future clinical trials. Future therapeutic strategies of RA for glomerular disease could include: 1) the development of retinoic acid receptor (RAR)α- and Kruppel-like factor 15 (KLF15)-specific agonists to avoid the side effects mediated by RARγ; 2) use of combination therapy with a low dose of RARα agonists and phosphodiesterase 4 (PDE4) inhibitors to avoid side effects associated with a high dose of RA; 3) possible use of a combination of RA with retinoic acid receptor responder protein 1 (RARRES1) inhibitors to avoid RARRES1-mediated podocyte toxicity.