An additive effect of eplerenone to ACE inhibitor on slowing the progression of diabetic nephropathy in the db/db mice.
An additive effect of eplerenone to ACE inhibitor on slowing the progression of diabetic nephropathy in the db/db mice.
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发表时间：
2016-03
影响因子：
2.2
通讯作者：
Guangyu Zhou;U. Johansson;Xiao-Rong Peng;K. Bamberg;Yufeng Huang
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作者：
Guangyu Zhou;U. Johansson;Xiao-Rong Peng;K. Bamberg;Yufeng Huang
尽管阻断肾素血管紧张素系统 (RAS) 已成为糖尿病肾病 (DN) 的标准治疗方法，但许多患者仍发现肾功能下降至终末期肾病。血浆醛固酮升高通常伴随着 RAS 阻断，这种现象被称为“醛固酮逃逸”，并激活盐皮质激素受体 (MR)。因此，我们研究了在 ACEI 中添加 MR 拮抗剂依普利酮是否会增强减缓 DN 进展的功效。未经治疗的未肾切除的糖尿病 db/db 小鼠在第 18 周至第 22 周期间出现进行性蛋白尿和肾小球硬化，与足细胞数量减少和肾纤维化标志物表达增加相关。依普利农 100 mg/kg BW/d 对蛋白尿、足细胞损伤和肾纤维化的治疗效果与最大有效剂量单独给予依那普利相似。在依那普利中添加依普利酮导致这些测量结果进一步减少。在糖尿病小鼠的疾病进展过程中，TNF-α、MCP-1、Nox2 和 p47phox 的肾脏表达以及肾脏 TBARS 水平（炎症和氧化应激的标志物）增加，单独给予依普利农或依那普利可降低这些水平，联合给予两种药物可进一步降低这些水平。然而，对血浆 K+ 没有治疗相关的影响。我们的结果表明，依普利酮可有效减缓 db/db 小鼠 DN 的进展，并且该效果与 ACEI 相加。在 ACEI 中添加对血浆 K+ 没有影响的 MR 拮抗剂，可以通过阻断因逃逸或糖尿病诱导而产生的醛固酮的影响，为进行性 DN 提供额外的肾脏保护。
Although blockade of the renin-angiotensin-system (RAS) has become standard therapy for diabetic nephropathy (DN), decline in kidney function towards end-stage renal disease is seen in many patients. Elevated plasma aldosterone often accompanies RAS blockade by a phenomenon known as "aldosterone escape" and activates the mineralocorticoid receptor (MR). We therefore examined whether addition of the MR antagonist eplerenone to an ACEI would enhance the efficacy in slowing the progression of DN. Untreated uninephrectomized diabetic db/db mice developed progressive albuminuria and glomerulosclerosis between weeks 18 and 22, associated with decreased number of podocytes and increased renal expression of fibrotic markers. The therapeutic effect of eplerenone at 100 mg/kg BW/d on albuminuria, podocyte injury and renal fibrosis was similar to that of enalapril given alone at maximally effective doses. Adding eplerenone to enalapril resulted in further reduction in these measurements. Renal expressions of TNF-α, MCP-1, Nox2 and p47phox and renal TBARS levels, markers of inflammation and oxidative stress, were increased during disease progression in diabetic mice, which were reduced by eplerenone or enalapril given alone and further reduced by the two drugs given in combination. However, there were no treatment related effects on plasma K+. Our results suggest that eplerenone is effective in slowing the progression of DN in db/db mice and that the effect is additive to an ACEI. The addition of an MR antagonist void of effects on plasma K+ to an ACEI may offer additional renoprotection in progressive DN via blocking the effects of aldosterone due to escape or diabetes-induction.