Diminazene aceturate prevents nephropathy by increasing glomerular ACE2 and AT2 receptor expression in a rat model of type1 diabetes

被引：66

作者：

Goru, Santosh Kumar ^{[1
]}

Kadakol, Almesh ^{[1
]}

Malek, Vajir ^{[1
]}

Pandey, Anuradha ^{[1
]}

Sharma, Nisha ^{[1
]}

Gaikwad, Anil Bhanudas ^{[1
]}

机构：

[1] Birla Inst Technol & Sci, Dept Pharm, Lab Mol Pharmacol, Pilani Campus, Pilani 333031, Rajasthan, India

来源：

BRITISH JOURNAL OF PHARMACOLOGY | 2017年 / 174卷 / 18期

关键词：

ANGIOTENSIN-CONVERTING ENZYME; OXIDATIVE STRESS; CONCISE GUIDE; RENAL ADAM17; IN-VIVO; ACTIVATION; PHARMACOLOGY; PATHOGENESIS; INHIBITION; PROTEIN;

D O I：

10.1111/bph.13946

中图分类号：

R9 [药学];

学科分类号：

1007 ;

摘要：

Background and PurposeOne of the protective actions of angiotensin converting enzyme-2 (ACE2) is the inactivation of angiotensin II. Expression and activity of ACE2 was reduced in glomeruli of diabetic patients and in animal models of diabetes. Recently the potential role of recombinant ACE2 administration in preventing diabetic nephropathy (DN) has been shown. Here we have tested the effects of the ACE2 activator, diminazene aceturate (DIZE), in a model of DN. Experimental ApproachMale Wistar rats were rendered diabetic using a single dose of streptozotocin (55mgkg(-1), i.p.). After 4weeks, diabetic animals were divided into experimental groups and treated with DIZE, at a low dose (5mgkg(-1)day(-1)), a high dose (15mgkg(-1)day(-1)) and the high dose with of the AT(2) receptor antagonist PD123319 (10mgkg(-1)day(-1)). At the end of the treatment , kidneys from all the groups were collected and processed separately for glomerular isolation, protein isolation, mRNA extraction and for immunohistochemical studies. Key ResultsTreatment with DIZE restored ACE2 expression in glomeruli and increased expression of AT(2) receptors in whole kidney and isolated glomeruli of diabetic animals. DIZE administration reduced angiotensin II levels and increased angiotensin-(1-7) levels in diabetic kidney. However, PD123319 treatment reversed all these actions of DIZE. Conclusions and ImplicationsDIZE treatment reduced diabetes-induced renal damage as shown by reduction of fibrosis and apoptosis. These protective actions of DIZE were blocked by the AT(2) receptor antagonist. Taken together, these results suggest that DIZE protected against DN through the ACE2/angiotensin-(1-7)/ AT(2) receptor axis.

引用

页码：3118 / 3130

页数：13

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