自分泌信号
内分泌学
成纤维细胞生长因子23
内科学
旁分泌信号
生物
成纤维细胞生长因子
纺神星
生长因子
细胞生物学
表皮生长因子
受体
信号转导
肾
甲状旁腺激素
医学
钙
作者
Pu Ni,Erica L. Clinkenbeard,Megan L. Noonan,Jerry Richardville,Jeanette N. McClintick,Takashi Hato,Danielle Janosevic,Ying-Hua Cheng,Tarek M. El-Achkar,Michael T. Eadon,Pierre C. Dagher,Kenneth E. White
标识
DOI:10.1016/j.kint.2020.10.024
摘要
Fibroblast 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.
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