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.