The core mechanism of hypertension-linked renal fibrosis: "RAAS-ROS-inflammation-fibrosis" axis.

Hypertension-linked renal fibrosis leads to the gradual loss of renal function and eventually progresses to end-stage renal failure, which exhibits poor clinical efficacy and is difficult to reverse. Therefore, clarifying the development mechanism of hypertension-linked renal fibrosis is crucial for its prevention and treatment. In this review, we conducted an in-depth exploration of the pivotal elements, along with their detailed mechanistic linkages in the pathogenesis of hypertension-linked renal fibrosis. It was found that the renin-angiotensin-aldosterone system (RAAS) is overactivated in hypertension. Angiotensin II (Ang II) and aldosterone (Aldo) jointly cause the abnormal accumulation of reactive oxygen species (ROS) by increasing the activity and expression of Nox2 and Nox4, inducing the inhibition and uncoupling of endothelial nitric oxide synthase (eNOS), enhancing expression of selected microRNAs (miRNAs), and reducing glucose-6-phosphate dehydrogenase (G6PD) expression. In turn, elevated ROS trigger renal inflammation by activating the mitogen-activated protein kinase (MAPK)-nuclear factor-kappa B (NF-κB) pathways as well as ferroptosis. Thereafter, renal inflammation can promote the process of renal fibrosis by activating the transforming growth factor β (TGF-β), platelet-derived growth factor (PDGF), and lysophosphatidic acid (LPA). This review not only emphasizes the core role of the mechanistic axis that plays a crucial role in the development of hypertension-driven renal fibrosis-the "RAAS-ROS-inflammation-fibrosis" axis-but also proposes promising therapeutic strategies targeting this axis, including modulating RAAS activity, controlling the increase in ROS, inhibiting inflammation, and blocking fibrotic progression. It aims to provide novel insights and potential therapeutic directions for hypertension-related renal fibrosis in the future.