HBEGF: an EGF-like growth factor with FGF23-like activity?
| Autor: | Edward R Smith, Tim D. Hewitson |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
medicine.medical_treatment 030232 urology & nephrology Biology Kidney urologic and male genital diseases Article Mice 03 medical and health sciences Paracrine signalling 0302 clinical medicine Human disease medicine Animals Mineral metabolism Autocrine signalling Gene chemistry.chemical_classification Minerals Epidermal Growth Factor Growth factor Cell biology Fibroblast Growth Factors Fibroblast Growth Factor-23 stomatognathic diseases 030104 developmental biology Enzyme chemistry Nephrology Heparin-binding EGF-like Growth Factor |
| Zdroj: | Kidney Int |
| ISSN: | 0085-2538 |
| DOI: | 10.1016/j.kint.2020.11.011 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|