Role of Angiotensin Converting Enzyme 2 and Mas in Diabetic Nephropathy

• Main Authors: Wan-Yu Hsiu, 徐婉瑜
• Other Authors: Li-Yueh Chuang
• Format: Others
• Language: zh-TW
• Published: 2007
• Online Access: http://ndltd.ncl.edu.tw/handle/92057330099695845417

碩士 === 高雄醫學大學 === 生物化學研究所碩士班 === 95 === Diabetic nephropathy (DN) is a major cause of end-stage renal disease (ESRD) and an important cause of morbidity and mortality in diabetic patients. DN is characterized by renal cell hypertrophy and accumulation of extracellular matrix, leading to renal fibrosis and finally ESRD. The pathogenesis of DN includes : hyperglycemia, advanced glycation end-product (AGE), renin-angiotensin system (RAS), cell cycle derangements, transforming growth factor-β (TGF-β), and oxidative stress, etc. Intrarenal RAS is activated in DN. ACE2, a novel membrane-bound ACE-related carboxy-monopeptidase, is also present in the tubules and glomeruli of kidney. ACE2 converts Ang I and Ang II to angiotensin-(1-7) (Ang-[1-7]). Ang-(1-7) specifically binds to Mas. Moreover, Ang-(1-7) acts as an endogenous inhibitor of Ang II, especially in conditions of activated RAS. Thus, ACE2 may counteract the action of Ang II via Ang-(1-7). However, the roles of ACE2, Ang-(1-7) and Mas in models of DN remain uncertain. Then, we used mesangial (M13) and proximal tubular cells (NRK-52E) to elucidate the roles of the above factors in DN. Results: Ang II, high glucose (HG) and type I transforming growth factor-β (TGF-β1) induced cell growth inhibition, hypertrophy and accumulation of collagen (extracellular matrix) in NRK-52E cells and M13 cells at ＞ 24 hrs. Moreover, both ACE2 and Mas mRNA were reduced in AII, HG and TGFβ1- treated NRK-52E cell at 72 hrs. Meanwhile, suppression of ACE2 enhanced HG- and TGFβ1-induced NRK-52E cell growth inhibition. Moreover, captopril (an ACE inhibitor), attenuated Ang II and TGF-β1-induced p21WAF/CIP1 and p27Kip1 expression in NRK-52E cell by increasing ACE2 activity and levels of Ang-(1-7). Additionally, in NRK-52E cell, Ang-(1-7) suppressed TGF-β1 promoter activity via Mas. In contrast, Ang-(1-7) attenuated TGF-β1 bioactivity in the absence of Mas. We concluded that the ACE2-Ang-(1-7)-Mas pathway may be impotant in the pathogenesis of DN.