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

Sci Rep. 2020 Oct 7;10(1):16683. doi: 10.1038/s41598-020-73099-9.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylcholine / pharmacology
  • Albumins / pharmacology
  • Aldosterone / pharmacology
  • Angiotensin II / pharmacology
  • Animals
  • Calcitonin Gene-Related Peptide / pharmacology
  • Cell Line
  • Cisplatin / pharmacology
  • Endothelin-1 / pharmacology
  • Female
  • Glucose / pharmacology
  • Humans
  • Kidney Diseases / metabolism*
  • Kidney Tubules, Collecting / cytology
  • Kidney Tubules, Collecting / drug effects
  • Kidney Tubules, Collecting / metabolism*
  • Lipopolysaccharides / pharmacology
  • Mice
  • Mice, Transgenic
  • Receptors, Retinoic Acid / metabolism*
  • Tretinoin / metabolism*
  • Vasopressins / pharmacology

Substances

  • Albumins
  • Endothelin-1
  • Lipopolysaccharides
  • Receptors, Retinoic Acid
  • Vasopressins
  • Angiotensin II
  • Aldosterone
  • Tretinoin
  • Glucose
  • Calcitonin Gene-Related Peptide
  • Acetylcholine
  • Cisplatin