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.

Keywords: angiotensin II; fibrosis; hypoxia-inducible factor; microRNA; reactive oxygen species; transforming growth factor-β.

Figure 1

Transforming growth factor (TGF)-β1 mediates angiotensin II (Ang II)-induced renal fibrosis. (a) Smad and non-Smad signaling contribute to the transcription of TGF-β1 target genes. Ang II via angiotensin type 1 receptor (AT1R) upregulates TGF-β1 expression. The growth factor binds to TGF-β receptor II (TβRII), which activates TβRI resulting in the phosphorylation of R-Smads (that is, Smad3). Kindlin-2 mediates the interaction of TβRI with Smad3 favoring Smad3 activation. The phosphorylated Smad3 binds to the Co-Smad, Smad4 forming the Smad complex that translocates into the nucleus and binds to Smad-binding elements (SBE) in promoter regions of target genes (that is, plasminogen activator inhibitor-1 (PAI-1), microRNAs (miRNAs)). TGF-β1 also triggers reactive oxygen species (ROS) that activate epidermal growth factor receptor (EGFR) signaling and p53, which in turn interacts with pSmad3 and other transcriptional cofactors sustaining gene induction. (b) TGF-β1 promotes fibrosis through the Smad3-dependent regulation of miRNA. Upregulation of miR-324-3p that represses Prep-dependent synthesis of the antifibrotic peptide N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP) amplifies TGF-β1 signaling.

Figure 2

Reactive oxygen species (ROS) mediate angiotensin II (Ang II)-induced renal interstitial fibrosis via hypoxia-inducible factor-1α (HIF-1α). Under normoxia, prolyl-4-hydroxylase domain 2 (PHD2) hydroxylates HIF-1α at specific proline residues allowing for recognition by pVHL/E3 ubiquitin ligase complex that ubiquinates and targets HIF-1α for proteasomal degradation. Ang II-induced H₂O₂, by limiting the availability of ferrous iron and ascorbate, inactivates PHD2 promoting HIF-1α stabilization. HIF-1α interacts with the HIF-1β forming an active heterodimer that translocates into the nucleus and binds to hypoxia-response elements (HRE) in promoter regions of the target genes (collagen I/III, TIMP-1, proliferating nuclear antigen (PCNA), vimentin). 2-OG, 2-oxoglutarate; Ub, ubiquitin.