Alteration in vitamin D catabolic enzyme 24-hydroxylase in aging renal tubules affect tubular transport function

Deficiency in vitamin D has been associated with aging-related diseases and an increased mortality risk. The kidneys are the main vitamin D producing organs. This study aimed to elucidate the alterations occurring in the renal vitamin D system during aging and their consequential impact on the expression of proximal tubular transporters. CYP24A1, CYP27B1, VDR, and key proximal tubule transporters were analyzed using GEO and Rodwell Aging Kidney databases. Age-related changes were confirmed in mouse and human kidney specimens via immunohistochemistry and Western blot. Cyp24a1 and Vdr were manipulated in mouse renal proximal tubular epithelial cells to assess changes in transporters expression. Chromatin immunoprecipitation (ChIP) assays confirmed the involvement of vitamin D response element (VDRE). Increased 24-OHase expression and decreased VDR, NPT2a, SGLT2, URAT1, and EAAT3 expression in aging human and rodent kidneys were verified using GEO datasets and immunohistochemistry and Western blot on biopsy specimen. VDR was positively associated with the key transporter genes. In vitro analysis demonstrated that 24-OHase negatively regulated the expression of Slc34a1, and Slc5a2 in mTEC via VDRE. The upregulation of 24-OHase in the aging kidney affected tubular transport function through VDR/VDRE interactions.