Ang II (Angiotensin II)–Induced FGFR1 (Fibroblast Growth Factor Receptor 1) Activation in Tubular Epithelial Cells Promotes Hypertensive Kidney Fibrosis and Injury

Abstract

Background: Elevated Ang II (angiotensin II) level leads to a range of conditions, including hypertensive kidney disease. Recent evidences indicate that FGFR1 (fibroblast growth factor receptor 1) signaling may be involved in kidney injuries. In this study, we determined whether Ang II alters FGFR1 signaling to mediate renal dysfunction. Methods: Human archival kidney samples from patients with or without hypertension were examined. Multiple genetic and pharmacological approaches were used to investigate FGFR1-mediated signaling in tubular epithelial NRK-52E cells in response to Ang II stimulation. C57BL/6 mice were infused with Ang II for 28 days to develop hypertensive kidney disease. Mice were treated with either adeno-associated virus expressing FGFR1 shRNA or FGFR1 inhibitor AZD4547. Results: Kidney specimens from subjects with hypertension and mice challenged with Ang II have increased FGFR1 activity in renal epithelial cells. Renal epithelial cells in culture initiate extracellular matrix programming in response to Ang II, through the activation of FGFR1, which is independent of both AT1R (angiotensin II receptor type 1) and AT2R (angiotensin II receptor type 2). The RNA sequencing analysis indicated that disrupting FGFR1 suppresses Ang II–induced fibrogenic responses in epithelial cells. Mechanistically, Ang II–activated FGFR1 leads to STAT3 (signal transducer and activator of transcription 3) activation, which is responsible for fibrogenic factor expression in kidneys. In the mouse model of hypertensive kidney disease, genetic knockdown of FGFR1 or pharmacological inhibition of its activity protected kidneys from dysfunction and fibrosis upon Ang II challenge. Conclusions: Our studies uncover a novel mechanism causing renal fibrosis in hypertension and indicate FGFR1 as a potential target to preserve renal function and integrity.

Fucoxanthin inhibits cardiac fibroblast transdifferentiation by alleviating oxidative stress through downregulation of BRD4

“…Ang II is an important active product of the renin-angiotensin-aldosterone system. It stimulates the release of epinephrine and norepinephrine, constricts blood vessels, and increases blood pressure [ 22 , 23 ]. Ang II promotes synthesis and inhibits degradation of ECM, leading to accumulation of ECM and ultimately inducing renal [ 24 ], pulmonary [ 25 ], and myocardial fibrosis [ 26 ].…”

Adhesion G Protein-Coupled Receptor Gpr126 (Adgrg6) Expression Profiling in Diseased Mouse, Rat, and Human Kidneys

“…Recently, we found that Gpr126 is expressed during kidney development [11,12]. To determine whether Gpr126 expression is altered during kidney disease, we performed RT-PCR analyses measuring the Gpr126 RNA levels in kidneys from animal models with mild (Ang II treatment, model of hypertensive nephropathy, mouse [24]) and severe kidney damage (I/R, model of AKI, rat [25]; UUO, model of interstitial fibrosis occurring in chronic renal failure, mouse [26]). While the Ang II treatment resulted in a modest increase (1.5-fold), I/R and UUO resulted in a marked upregulation of Gpr126 expression (2.5-and 8-fold, respectively, Figure S1).…”

Epithelial–mesenchymal plasticity in kidney fibrosis

“…Angiotensin‐II (Ang‐II) is a small peptide hormone derived from angiotensinogen through the enzymatic cleavage cascade (Yi et al, 2022). Several studies have demonstrated that Ang‐II is a profibrotic contributor and plays role in the pathogenesis of kidney fibrosis (Lyu, Li, Wu, & Hao, 2019; Wang et al, 2018; Xu et al, 2017, 2022). Ang‐II mediates kidney fibrogenesis by TGF‐β/Smad3 pathway activation (Lyu et al, 2019; Wu, Wang, Yu, & Lan, 2022).…”