간섬유화 발생기전에서 레닌 안지오텐신 시스템과 발생산소기의 역할

• Published in: Clinical and molecular hepatology 2011-03, Vol.17 (1s), p.6
• Main Author: 백용한
• Format: Article
• Language: Korean
• Subjects: Hepatic fibrosis; Hepatic stellate cell; NADPH oxidase; Reactive oxygen species; Renin angiotensin system
• ISSN: 2287-2728

The renin-angiotensin system (RAS) is a master regulator of human physiology that plays a key role in maintaining blood pressure homeostasis, as well as fluid and salt balance in mammals through coordinated effects on the heart, blood vessels and kidneys. In the classic pathway of RAS, renin cleaves the liver-derived precursor peptide angiotensinogen into the decapeptide Ang I. Ang I is further hydrolyzed into the octapeptide Ang II by the angiotensin converting enzyme (ACE), which represents the main effector peptide of the RAS. The discovery of ACE homologue ACE2 adds a new complexity to the RAS. ACE2 degrades Ang II to Ang1-7 which exerts effects opposite to those of Ang II through its receptor Mas. Reactive oxygen species (ROS) is involved as key secondary messengers in numerous signaling pathways including transcriptional regulation, differentiation and proliferation to oncogenic transformation, activation of programmed cell death. NADPH oxidase (NOX) is a multi-protein complex that generates ROS in response to a wide range of stimuli including TNFα, IL-1β, angiotensin II. Until now 7 NOX homologues have been identified. Wild-type HSCs express the mRNAs for both NOX1 and NOX2. HSCs also express other NOX components including p47phox, p67phox, NOXO1, NOXA1, and Rac1. NOX components including NOX1 and NOX2 are upregulated in activated HSCs compared to quiescent HSCs. Hepatic ROS generation and fibrosis was significantly attenuated in NOX1-deficient and NOX2-deficient mice compared to in WT mice. These results strongly suggest that both phagocytic NADPH oxidase (NOX2) and non-phagocytic NADPH oxidase (NOX1) contribute to hepatic fibrosis. These new insights provide the rationale to target specific components of NOX complexes as novel therapies in hepatic fibrosis without blocking the NOX complex required for innate immunity.