Studying the Association of Renin-Angiotensin-Aldosterone System and Renal, Cardiovascular Disease by Animal Experiment and Health Insurance Database Analysis

• Main Authors: Yang, Chung-Wei, 楊忠煒
• Other Authors: Lin, Chih-Sheng
• Format: Others
• Language: en_US
• Published: 2017
• Online Access: http://ndltd.ncl.edu.tw/handle/92gv63

博士 === 國立交通大學 === 生物科技學系 === 106 === There are two parts of topics performed in this study. In the first part, we studied the effects of angiotensin receptor blockers (ARBs) on decreasing the risk of major adverse cardiovascular events (MACEs) in patients with end-stage renal disease (ESRD) on maintenance dialysis. In the second part, we studied the role of angiotensin-related enzymes, especially the activity of chymase, of renin-angiotensin-aldosterone system (RAAS) in nephropathy induced by aristolochic acid I (AAI). Part I of the study: MACEs are the leading cause of morbidity and mortality in patients with end-stage renal disease (ESRD) on maintenance hemodialysis or peritoneal dialysis. Many studies have proved that ARBs, a class of antihypertensive drugs, can reduce the risk of MACEs in the people with normal kidney function or with impaired kidney function without dialysis yet. There are no clear evidences between benefits and risks on dialysis patients using ARBs, so we conducted a study to clarify whether ARBs therapy could also attenuate this risk in patients with ESRD on maintenance dialysis. We used the National Health Insurance Research Database (NHIRD) for this nationwide matched cohort study. Patients were selected under the International Classification of Diseases, Revision 9 (ICD-9) codes, including disease codes and treatment codes. Patients undergoing maintenance dialysis without a history of MACEs and without use of ARBs within the latest 6 months prior to enrollment were recruited. A total of 1,800 patients was enrolled in this study, 1,061 had never used ARBs, while 224 had used them for 1–90 days, and 515 had used them for more than 90 days. This study showed that ARBs can significantly decrease the incidences of MACEs and decrease the demands of invasive procedures of PTCA and PTA for AMI and PAD respectively. The time needed to bring above benefits depended on cumulative prescription days of ARBs in different subgroups：(1) hypertensive patients without diabetes mellitus and hyperlipidemia, it worked when cumulative prescription days exceeds 1,095 days; (2) patients with diabetes mellitus needed more than 365 days; (3) patients with hyperlipidemia needed more 365 days also, but the benefits vanished after 1,095 days; (4) patient with diabetes mellitus and hyperlipidemia, only above 91 days needed and the benefit sustained. Based on this research that ARBs could significantly reduce the occurrence of MACEs, and decrease the demands of invasive procedures, we strongly suggest that ARBs should be prescribed as the first line of antihypertensive to the hypertensive, without MACEs before, dialysis patients who are older than 50, especially coexisting with diabetes mellitus and hyperlipidemia. Based on this study, we think we should furtherly make a randomized controlled trial to confirm these benefits. Part II of the study: Angiotensin converting enzyme (ACE) is the primary enzyme to convert angiotensin I (Ang I) to angiotensin II (Ang II) in RAAS. However, some studies had showed that chymase may play an important role to catalyze Ang I to Ang II, independent of ACE, in kidney disease progress. The aim of this research was to know whether chymase may play the crucial role in AA-induced nephropathy. We used male ACE2 knockout (ACE2 KO) mice (ACE2-/y) for this study. The mice were treated with AAI via intraperitoneal (i.p.) injection and the accumulated AAI dosage was 100 mg/kg/4weeks. The animals were sacrificed 2 weeks and 4 weeks later for kidney disease development, then urine, blood and kidney tissues were sampled for further assays of biochemical, pathological and enzymatic activities. We found that the AAI-treated mice decreased body weight, and increased serum creatinine and blood urea nitrogen levels. In the renal tissue sections, we found high amount of inflammatory cells by hematoxylin and eosin (H&E) stain, and much fibrosis in the tubulointerstitial tissue by Masson’s trichrome stain. The activities of matrix metalloproteinase-2 (MMP-2) increased but MMP-9 decreased in these AAI-treated mice. Most importantly, we found a significantly increased chymase activity in the kidney tissues of these mice, but the ACE activity did not show significant changes, which indicated the chymase may play the important role in the nephropathy progress. We can conduct a new drug research to find some anti-chymase substances to ameliorate the kidney damages.