Effects of renin-angiotensin system blockade on islet function in diabetic rats.
OBJECTIVE
To investigate the effects of renin-angiotensin system (RAS) blockade on islet structure and function in diabetic rats, and its mechanisms.


METHODS
Diabetic rat models were created by high-fat high-caloric laboratory chow plus small dose (30 mg/kg) streptozotocin ip injection. After 8-week intervention with perindopril (AE, no.=10) or valsartan (AR, no.=10), all the animals' islet function was evaluated by iv glucose tolerance test. Pancreases were stained by immunohistochemistry technique to qualitative and/or quantitative analysis the content of insulin, inducible nitric oxide synthase (iNOS), transforming growth factors-beta1 (TGF-beta1) in islets. The apoptosis of islet cells was detected by transferase-mediated dUTP nick-end labeling dUTP nick end labeling (TUNEL). The expression level of angiotensinogen (AGT) and insulin mRNA in islets were detected by RT-PCR.


RESULTS
Compared with normal control group (NC, no.=10), area under the curve of insulin from 0 to 10 min (AUCI0-10) of diabetes group (DM, no.=8) was decreased by 66.9%, the relative expression of local AGT was increased by 69.2%, the insulin relative concentration (IRC) of beta-cell and the expression of insulin mRNA were decreased significantly, the amount of apoptotic cells in unit islet area was increased by 2.1 times, the relative content of iNOS and TGF-beta1 positive cell relative volume (TRV) was increased by 23.0% and 2.52 times, respectively (all p<0.01). Compared with DM group, AUCI0-10 of AE and AR group was increased by 41.4% and 33.2%, respectively; the relative expression of local AGT was decreased by 21.4% and 23.4%, respectively; IRC and the expression of insulin mRNA were increased significantly; the amount of apoptotic islet cells was decreased by 79.0% and 36.2%, respectively; the relative content of iNOS was decreased by 16.5% and 18.9%, respectively; TRV was decreased by 43.8% and 35.6%, respectively (all p<0.01). There were no significant differences between group AE and AR.


CONCLUSIONS
Blockade of RAS may improve diabetic rats islet function via the amelioration of intra-islets oxidative stress, fibrosis and apoptosis.
Yuan
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L
Department of Endocrinology, Union Hospital, Tongji Medical College of HuaZhong Science & Technology University, 1277 Jiefang Road, Wuhan City, China. yuanli18cn@yahoo.com.cn
Li
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Xu
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Qi
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D000808:Angiotensinogen / Q000096:biosynthesis; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D003921:Diabetes Mellitus, Experimental / Q000503:physiopathology*; D005951:Glucose Tolerance Test; D020287:In Situ Nick-End Labeling; D007515:Islets of Langerhans / Q000187:drug effects / Q000503:physiopathology*; D008297:Male; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D020913:Perindopril / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D012084:Renin-Angiotensin System / Q000187:drug effects*; D013777:Tetrazoles / Q000494:pharmacology; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D014633:Valine / Q000031:analogs & derivatives / Q000494:pharmacology; D000068756:Valsartan
D013777:Tetrazoles; D053773:Transforming Growth Factor beta1; D000808:Angiotensinogen; D000068756:Valsartan; D052247:Nitric Oxide Synthase Type II; D014633:Valine; D020913:Perindopril