Collecting duct cells show differential retinoic acid responses to acute versus chronic kidney injury stimuli

Abstract

Retinoic acid (RA) activates RA receptors (RAR), resulting in RA response element (RARE)-dependent gene expression in renal collecting duct (CD). Emerging evidence supports a protective role for this activity in acute kidney injury (AKI) and chronic kidney disease (CKD). Herein, we examined this activity in RARE-LacZ transgenic mice and by RARE-Luciferase reporter assays in CD cells, and investigated how this activity responds to neurotransmitters and mediators of kidney injury. In RARE-LacZ mice, Adriamycin-induced heavy albuminuria was associated with reduced RA/RAR activity in CD cells. In cultured CD cells, RA/RAR activity was repressed by acetylcholine, albumin, aldosterone, angiotensin II, high glucose, cisplatin and lipopolysaccharide, but was induced by aristolochic acid I, calcitonin gene-related peptide, endothelin-1, gentamicin, norepinephrine and vasopressin. Compared with age-matched normal human CD cells, CD-derived renal cystic epithelial cells from patients with autosomal recessive polycystic kidney disease (ARPKD) had significantly lower RA/RAR activity. Synthetic RAR agonist RA-568 was more potent than RA in rescuing RA/RAR activity repressed by albumin, high glucose, angiotensin II, aldosterone, cisplatin and lipopolysaccharide. Hence, RA/RAR in CD cells is a convergence point of regulation by neurotransmitters and mediators of kidney injury, and may be a novel therapeutic target.

Defining cellular complexity in human autosomal dominant polycystic kidney disease by multimodal single cell analysis

“…Recent lines of evidence suggest that the retinoic acid signaling pathway mediated by RAR in the collecting duct plays a protective role in kidney injury 44 . Interestingly, retinoic acid signaling was shown to be also activated by vasopressin in collecting duct cells 45 , providing evidence of crosstalk between cAMP signaling and retinoic acid signaling pathways. The binding motifs for CREB1 and retinoic acid receptors were enriched in ADPKD cells (Fig.…”

Defining cellular complexity in human autosomal dominant polycystic kidney disease by multimodal single cell analysis

“…Aberrant activation of the retinoic acid signaling pathway may promote rather cyst growth and interstitial remodeling in ADPKD kidneys. This pathway was also found to be activated by vasopressin 59 , a pathway whose inhibition slows progression in ADPKD.…”

“…Recent lines of evidence suggest that the retinoic acid signaling pathway mediated by RAR in the collecting duct plays a protective role in kidney injury 58 . Interestingly, retinoic acid signaling was shown to be also activated by vasopressin in collecting duct cells 59 , providing evidence of crosstalk between cAMP signaling and retinoic acid signaling pathways. The binding motifs for CREB1 and retinoic acid receptors were enriched in ADPKD cells (Fig.…”

A retinoic acid receptor β2 agonist protects against alcohol liver disease and modulates hepatic expression of canonical retinoid metabolism genes

“…As previously discussed, RA synthesis and signaling may be an adaptive, early hepatoprotective response, but it is also conceivable that with chronic EtOH‐consumption, reductions in RA‐signaling from chronic hepatic retinoid depletion may become maladaptive and contribute to the progression of ALD. Precedent for this has been documented with the renal protective actions of RA:RAR‐signaling in acute kidney injury (AKI), which eventually become reduced due to RA depletion in chronic kidney disease 67 …”

“…Precedent for this has been documented with the renal protective actions of RA:RAR-signaling in acute kidney injury (AKI), which eventually become reduced due to RA depletion in chronic kidney disease. 67 Although AC261 is reported to be a highly selective agonist for RARβ2 and thus a potential stimulator of RA: RARβ2 signaling, 23 and we measured reductions in ALD disease markers in EtOH-AC versus EtOH mice (Figure 1K-O), we do not understand why the EtOH-AC mice show reduced hepatic transcripts of RARβ and RARβ2 (Figure S6B,C) and selective modulation of other well-defined RA-target genes, such as CYP261A1, CYP26B1, LRAT, and RBP1, compared to EtOH mice (Figures S3A,O and S6B,C).…”