Cardiovascular effects of renal distal tubule deletion of the fgf receptor 1 gene

Xiaobin Han, Jed Ross, Ganesh Kolumam, Min Pi, Junichiro Sonoda, Gwendalyn King, Leigh Quarles

Research output: Contribution to journalArticle

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Abstract

The bone-derived hormone fibroblast growth factor–23 (FGF-23) activates complexes composed of FGF receptors (FGFRs), including FGFR1, and a-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 FGFR1 in the DT (FGFR1DT-cKO mice) resulted in left ventricular hypertrophy (LVH) and decreased kidney expression of a-Klotho in association with enhanced BP, decreased expression of angiotensin converting enzyme 2, and increased expression of the Na+-K+-2Cl2 cotransporter. Notably, recombinant FGF-23 administration similarly decreased the kidney expression of a-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 Hyp mouse model of excess FGF-23, but did not induce a response in FGFR1DT-cKO mice. The hearts of FGFR1DT-cKO 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 Hyp 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.

Original languageEnglish (US)
Pages (from-to)69-80
Number of pages12
JournalJournal of the American Society of Nephrology
Volume29
Issue number1
DOIs
StatePublished - Jan 1 2018

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Distal Kidney Tubule
Kidney
Left Ventricular Hypertrophy
Fibroblasts
Knockout Mice
Genes
Hypertension
Growth
Transient Receptor Potential Channels
Fibroblast Growth Factor Receptors
Growth Hormone
Anti-Idiotypic Antibodies
Hemodynamics
Sodium
Monoclonal Antibodies
Bone and Bones

All Science Journal Classification (ASJC) codes

  • Nephrology

Cite this

Cardiovascular effects of renal distal tubule deletion of the fgf receptor 1 gene. / Han, Xiaobin; Ross, Jed; Kolumam, Ganesh; Pi, Min; Sonoda, Junichiro; King, Gwendalyn; Quarles, Leigh.

In: Journal of the American Society of Nephrology, Vol. 29, No. 1, 01.01.2018, p. 69-80.

Research output: Contribution to journalArticle

Han, Xiaobin ; Ross, Jed ; Kolumam, Ganesh ; Pi, Min ; Sonoda, Junichiro ; King, Gwendalyn ; Quarles, Leigh. / Cardiovascular effects of renal distal tubule deletion of the fgf receptor 1 gene. In: Journal of the American Society of Nephrology. 2018 ; Vol. 29, No. 1. pp. 69-80.
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