Department of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee.
Department of Molecular Biology and Biomedical Imaging, Genentech, South San Francisco, California; and.
J Am Soc Nephrol. 2018 Jan;29(1):69-80. doi: 10.1681/ASN.2017040412. Epub 2017 Oct 9.
The bone-derived hormone fibroblast growth factor-23 (FGF-23) activates complexes composed of FGF receptors (FGFRs), including FGFR1, and -Klotho in the kidney distal tubule (DT), leading to increased sodium retention and hypertension. However, the role of FGFR1 in regulating renal processes linked to hypertension is unclear. Here, we investigated the effects of selective FGFR1 loss in the DT. Conditional knockout (cKO) of in the DT ( mice) resulted in left ventricular hypertrophy (LVH) and decreased kidney expression of -Klotho in association with enhanced BP, decreased expression of angiotensin converting enzyme 2, and increased expression of the Na-K-2Cl cotransporter. Notably, recombinant FGF-23 administration similarly decreased the kidney expression of -Klotho and induced LVH in mice. Pharmacologic activation of FGFR1 with a monoclonal anti-FGFR1 antibody (R1MAb1) normalized BP and significantly attenuated LVH in the mouse model of excess FGF-23, but did not induce a response in mice. The hearts of mice showed increased expression of the transient receptor potential cation channel, subfamily C, member 6 (TRPC6), consistent with cardiac effects of soluble Klotho deficiency. Moreover, administration of recombinant soluble Klotho lowered BP in the mice. Thus, FGFR1 in the DT regulates systemic hemodynamic responses opposite to those predicted by the actions of FGF-23. These cardiovascular effects appear to be mediated by paracrine FGF control of kidney FGFR1 and subsequent regulation of soluble Klotho and TRPC6. FGFR1 in the kidney may provide a new molecular target for treating hypertension.
骨源激素成纤维细胞生长因子 23（FGF-23）在肾脏远曲小管（DT）中激活由 FGFR 受体（FGFRs）组成的复合物，包括 FGFR1 和 -Klotho，导致钠潴留增加和高血压。然而，FGFR1 在调节与高血压相关的肾脏过程中的作用尚不清楚。在这里，我们研究了选择性 FGFR1 在 DT 中的缺失的影响。在 DT 中条件敲除（cKO）（小鼠）导致左心室肥厚（LVH）和肾脏 -Klotho 表达降低，同时伴有血压升高、血管紧张素转换酶 2 表达降低和 Na-K-2Cl 共转运蛋白表达增加。值得注意的是，重组 FGF-23 给药同样降低了肾脏 -Klotho 的表达并在小鼠中诱导 LVH。用单克隆抗 FGFR1 抗体（R1MAb1）药理学激活 FGFR1 可使 FGF-23 过量的 小鼠模型中的血压正常化并显著减轻 LVH，但在 小鼠中没有引起反应。小鼠的心脏显示瞬态受体电位阳离子通道亚家族 C 成员 6（TRPC6）的表达增加，与可溶性 Klotho 缺乏的心脏效应一致。此外，重组可溶性 Klotho 的给药可降低 小鼠的血压。因此，DT 中的 FGFR1 调节全身血液动力学反应与 FGF-23 的作用相反。这些心血管作用似乎是通过肾 FGFR1 的旁分泌 FGF 控制和随后调节可溶性 Klotho 和 TRPC6 介导的。肾脏中的 FGFR1 可能为治疗高血压提供新的分子靶标。
