title: Key fibrogenic mediators: old players. Renin-angiotensin system.
abstract: Interstitial fibrosis represents the final common pathway of any form of progressive renal disease. The severity of tubular interstitial damage is highly correlated to the degree of decline of renal function, even better than the glomerular lesions do. Angiotensin II (Ang II), the main effector of the renin-angiotensin system, is a critical promoter of fibrogenesis. It represents a nexus among glomerular capillary hypertension, barrier dysfunction, and renal tubular injury caused by abnormally filtered proteins. Transforming growth factor (TGF)-β1 and reactive oxygen species (ROS) are the key mediators of the pro-fibrotic effect of Ang II causing apoptosis and epithelial-to-mesenchymal transition of the renal tubular epithelium. Recent studies link fibrosis to changes of microRNA (miRNA) modulated by Ang II through TGF-β1, unraveling that antifibrotic action of Ang II antagonism is attributable to epigenetic control of fibrosis-associated genes. Other mechanisms of Ang II-induced fibrosis include ROS-dependent activation of hypoxia-inducible factor-1. Finally, Ang II via angiotensin type 1 receptor regulates the activation and transdifferentiation of pericytes and fibrocytes into scar-forming myofibroblasts. Detachment and phenotypic changes of the former can lead to the loss of peritubular capillaries and also contribute to hypoxia-dependent fibrosis.
authors: IRCCS-Istituto di Ricerche Farmacologiche 'Mario Negri', Centro Anna Maria Astori, Science and Technology Park Kilometro Rosso , Bergamo, Italy.
authors: Daniela
authors: D
authors: Macconi
authors: IRCCS-Istituto di Ricerche Farmacologiche 'Mario Negri', Centro Anna Maria Astori, Science and Technology Park Kilometro Rosso , Bergamo, Italy ; Unit of Nephrology and Dialysis, Azienda Ospedaliera Papa Giovanni XXIII , Bergamo, Italy.
authors: Giuseppe
authors: G
authors: Remuzzi
authors: IRCCS-Istituto di Ricerche Farmacologiche 'Mario Negri', Centro Anna Maria Astori, Science and Technology Park Kilometro Rosso , Bergamo, Italy.
authors: Ariela
authors: A
authors: Benigni
keywords: angiotensin II; fibrosis; hypoxia-inducible factor; microRNA; reactive oxygen species; transforming growth factor-β