Spironolactone exhibits direct renoprotective effects and inhibits renal renin-angiotensin-aldosterone system in diabetic rats
Spironolactone exhibits direct renoprotective effects and inhibits renal renin-angiotensin-aldosterone system in diabetic rats
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DOI：
10.1016/j.ejphar.2008.06.019
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发表时间：
2008-07-28
影响因子：
5
通讯作者：
Nakata, Tetsuo
中科院分区：
文献类型：
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作者：
Taira, Masateru;Toba, Hiroe;Nakata, Tetsuo
据报道，醛固酮本身参与介导肾损伤，并且已证实醛固酮合酶CYP11B2基因、蛋白质和醛固酮的产生局部存在于肾脏中。为了检验盐皮质激素受体拮抗剂可能改善糖尿病肾病以及抑制肾脏 CYP11B2 表达可能与这些肾脏保护作用相关的假设，通过给未切除肾的糖尿病大鼠灌胃给予螺内酯（50 mg/kg/天）3 周。链脲佐菌素（55 mg/kg，静脉注射）显着增加肾小球和肾小管间质区域的尿蛋白排泄和胶原蛋白沉积，螺内酯治疗可减弱这些作用。 RT-PCR和蛋白质印迹分析显示，在未肾切除的糖尿病大鼠肾脏中，肾脏中胶原蛋白I/IV、转化生长因子-β、NADPH氧化酶和盐皮质激素受体以及盐皮质激素受体蛋白的mRNA表达增强，并且螺内酯抑制了这些分子的过度表达。糖尿病大鼠肾血管紧张素转换酶被激活并过度表达，螺内酯可抑制这些变化。我们证明螺内酯可以防止链脲佐菌素诱导的肾脏 CYP11B2 mRNA 含量增加。用胰岛素控制血糖水平也减弱了 CYP11B2 mRNA 的肾脏表达。另一方面，本研究中螺内酯的治疗不会影响未切除肾的链脲佐菌素诱导的糖尿病大鼠的血糖水平或血压。这些结果表明，螺内酯对未切除肾的链脲佐菌素诱导的糖尿病大鼠具有肾脏保护作用，并抑制肾脏局部肾素-血管紧张素-醛固酮系统，如 ACE 表达和高血糖诱导的 CYP11B2 过度表达。 (c) 2008 Elsevier B.V. 保留所有权利。
Aldosterone itself has been reported to participate in mediating renal injury, and it was confirmed that the aldosterone synthase CYP11B2 gene, protein, and alclosterone production are locally present in the kidney. To test the hypothesis that a mineralocorticoid receptor antagonist might ameliorate diabetic nephropathy and the inhibition of renal CYP11B2 expression might be associated with these renoprotective effects, spironolactone (50 mg/kg/day) was administered by gavage to uninephrectomized diabetic rats for 3 weeks. Streptozotocin (55 mg/kg, i.v.) significantly increased urinary protein excretion and collagen deposition in glomerular and tubulointerstitial areas in the kidney, which were attenuated by spironolactone treatment. RT-PCR and Western blot analysis revealed that the expression of mRNA for collagen I/IV, transforming growth factor-beta, NADPH oxidase and mineralocorticoid receptor and the mineralocorticoid receptor protein in the kidney was enhanced in the uninephrectomized diabetic rat kidney and that the overexpression of these molecules was suppressed by spironolactone. Renal angiotensin converting enzyme was activated and overexpressed in diabetic rats, and spironolactone inhibited these changes. We demonstrated that spironolactone prevented the streptozotocin-induced increase in the renal CYP11B2 mRNA content. Controlling blood glucose level with insulin also attenuated the renal expression of mRNA for CYP11B2. On the of-her hand, the treatment of spironolactone in the present study did not affect blood glucose level or blood pressure in uninephrectomized streptozotocin-induced diabetic rats. These results suggest that spironolactone exerted renoprotective effects in uninephrectomized streptozotocin-induced diabetic rats and inhibited local renin-angiotensin-aldosterone system, such as the ACE expression and the hyperglycemia-induced overexpression of CYP11B2, in the kidney. (c) 2008 Elsevier B.V. All rights reserved.