Ni, PuClinkenbeard, Erica L.Noonan, Megan L.Richardville, Joseph M.McClintick, JeanetteHato, TakashiJanosevic, DanielleCheng, Ying-HuaEl-Achkar, Tarek M.Eadon, Michael T.Dagher, Pierre C.White, Kenneth E.2023-05-192023-05-192021Ni P, Clinkenbeard EL, Noonan ML, et al. Targeting fibroblast growth factor 23-responsive pathways uncovers controlling genes in kidney mineral metabolism. Kidney Int. 2021;99(3):598-608. doi:10.1016/j.kint.2020.10.024https://hdl.handle.net/1805/33154Fibroblast Growth Factor 23 (FGF23) is a bone-derived hormone that reduces kidney phosphate reabsorption and 1,25(OH)2 vitamin D synthesis via its required co-receptor alpha-Klotho. To identify novel genes that could serve as targets to control FGF23-mediated mineral metabolism, gene array and single-cell RNA sequencing were performed in wild type mouse kidneys. Gene array demonstrated that heparin-binding EGF-like growth factor (HBEGF) was significantly up-regulated following one-hour FGF23 treatment of wild type mice. Mice injected with HBEGF had phenotypes consistent with partial FGF23-mimetic activity including robust induction of Egr1, and increased Cyp24a1 mRNAs. Single cell RNA sequencing showed overlapping HBEGF and EGF-receptor expression mostly in the proximal tubule, and alpha-Klotho expression in proximal and distal tubule segments. In alpha-Klotho-null mice devoid of canonical FGF23 signaling, HBEGF injections significantly increased Egr1 and Cyp24a1 with correction of basally elevated Cyp27b1. Additionally, mice placed on a phosphate deficient diet to suppress FGF23 had endogenously increased Cyp27b1 mRNA, which was rescued in mice receiving HBEGF. In HEK293 cells with stable alpha-Klotho expression, FGF23 and HBEGF increased CYP24A1 mRNA expression. HBEGF, but not FGF23 bioactivity was blocked with EGF-receptor inhibition. Thus, our findings support that the paracrine/autocrine factor HBEGF could play novel roles in controlling genes downstream of FGF23 via targeting common signaling pathways.en-USPublisher PolicyAlpha-KlothoKidneyMineral metabolismArticle