PR001894 (Project)

Description:Chronic kidney disease (CKD) is characterized by a gradual loss of kidney function and affects ca. 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 retinoic acid receptors (RAR alpha, beta, gamma). RARalpha levels are decreased in a mouse model of diabetic nephropathy (DN) and restored with RA administration; additionally, RA treatment reduces fibrosis. We developed a mouse model in which a spatiotemporal (tamoxifen-inducible) deletion of RARalpha 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 (3-4.5 months) of RARalpha deletion include increased PT secretion of transforming growth factor beta (TGF-beta1), inflammation, interstitial fibrosis, and decreased kidney function, all of which are major features of human CKD. Therefore, RARalpha’s actions in proximal tubules (PTs) are crucial for PT homeostasis, and loss of RARalpha causes injury and a key CKD phenotype.