Angiotensin II-induced fibrosis is mediated by activation of FGFR1 pathway in renal epithelial cells: Attenuation by chimeric peptide

Renal fibrosis is a prominent pathophysiologic change seen with the progression of chronic kidney disease. Angiotensin II (Ang II), the central peptide of the renin-angiotensin aldosterone system (RAAS), is known to cause fibrosis under various disease conditions. Fibroblast Growth Factor receptor-1 (FGFR1) plays a critical role in epithelial to mesenchymal transition and tubulointerstitial fibrosis, but its role in Ang II-induced fibrosis in renal epithelial cells (RECs) and renal fibroblasts (RFbs) remains poorly understood. Our study aimed to investigate the role of FGFR1 in Ang II-induced fibrosis in both REC, RFbs and explore the potential of chimeric peptide (CP) in attenuating it. We developed a time-dependent in vitro fibrosis model using REC exposed to Ang II and analyzed the expression of FGFR1 and fibrotic markers by qPCR. Oxidative stress and profibrotic markers were measured using confocal imaging and flow cytometry. In RFbs, we also examined fibrotic cell proliferation and Collagen deposition using proliferation assays and Sirius red staining. Our findings show that Ang II significantly increases FGFR1, AT₁ receptor, and oxidative stress markers through the ERK/MAPK pathway. Simultaneously, it downregulates MAS1 and pGC-A expression, protective pathways of the RAAS system. However, co-treatment with CP, which targets MAS1 and pGC-A, reversed the harmful changes caused by Ang II. In conclusion, our study suggests that Ang II-induced fibrosis is mediated through FGFR1, AT₁ receptor activation, and CP can more effectively counteract these effects than individual peptides by dual activation of the protective pathways of the RAAS system.

Angiotensin II; Chimeric peptide; FGFR1; Renal epithelial cells; Renal fibroblasts; Renal fibrosis; Renin angiotensin aldosterone system.