Retinoic acid receptor α activity in proximal tubules prevents kidney injury and fibrosis.

TitleRetinoic acid receptor α activity in proximal tubules prevents kidney injury and fibrosis.
Publication TypeJournal Article
Year of Publication2024
AuthorsDiKun KM, Tang X-H, Fu L, Choi ME, Lu C, Gudas LJ
JournalProc Natl Acad Sci U S A
Volume121
Issue7
Paginatione2311803121
Date Published2024 Feb 13
ISSN1091-6490
KeywordsAnimals, Disease Models, Animal, Fibrosis, Humans, Kidney, Kidney Tubules, Proximal, Mice, Renal Insufficiency, Chronic, Retinoic Acid Receptor alpha, Tretinoin
Abstract

Chronic kidney disease (CKD) is characterized by a gradual loss of kidney function and affects ~13.4% of the global population. Progressive tubulointerstitial fibrosis, driven in part by proximal tubule (PT) damage, is a hallmark of late stages of CKD and contributes to the development of kidney failure, for which there are limited treatment options. Normal kidney development requires signaling by vitamin A (retinol), which is metabolized to retinoic acid (RA), an endogenous agonist for the RA receptors (RARα, β, γ). RARα levels are decreased in a mouse model of diabetic nephropathy and restored with RA administration; additionally, RA treatment reduced fibrosis. We developed a mouse model in which a spatiotemporal (tamoxifen-inducible) deletion of RARα in kidney PT cells of adult mice causes mitochondrial dysfunction, massive PT injury, and apoptosis without the use of additional nephrotoxic substances. Long-term effects (3 to 4.5 mo) of RARα deletion include increased PT secretion of transforming growth factor β1, inflammation, interstitial fibrosis, and decreased kidney function, all of which are major features of human CKD. Therefore, RARα's actions in PTs are crucial for PT homeostasis, and loss of RARα causes injury and a key CKD phenotype.

DOI10.1073/pnas.2311803121
Alternate JournalProc Natl Acad Sci U S A
PubMed ID38330015
PubMed Central IDPMC10873609
Grant ListR01 DK113088 / DK / NIDDK NIH HHS / United States
T32 CA062948 / CA / NCI NIH HHS / United States
R01DK113088 / GF / NIH HHS / United States
5T32CA062948-26 / BC / NCI NIH HHS / United States