Title | Retinoic acid receptor α activity in proximal tubules prevents kidney injury and fibrosis. |
Publication Type | Journal Article |
Year of Publication | 2024 |
Authors | DiKun KM, Tang X-H, Fu L, Choi ME, Lu C, Gudas LJ |
Journal | Proc Natl Acad Sci U S A |
Volume | 121 |
Issue | 7 |
Pagination | e2311803121 |
Date Published | 2024 Feb 13 |
ISSN | 1091-6490 |
Keywords | Animals, 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. |
DOI | 10.1073/pnas.2311803121 |
Alternate Journal | Proc Natl Acad Sci U S A |
PubMed ID | 38330015 |
PubMed Central ID | PMC10873609 |
Grant List | R01 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 |