Department of Internal Medicine, Research Institute of Clinical Medicine and Diabetes Research Center, Chonbuk National University Medical School, Deokjin-gu, Jeonju 561-712, Republic of Korea.
Int J Mol Med. 2013 Dec;32(6):1293-302. doi: 10.3892/ijmm.2013.1508. Epub 2013 Sep 25.
Metabolic syndrome is characterized by insulin resistance, dyslipidemia and hypertension. These metabolic changes contribute to the development of obesity-induced kidney injury. AMP-activated protein kinase (AMPK) is a ubiquitous enzyme that is involved in the cellular metabolic response to metabolic stress. Metformin, an AMPK activator, has been reported to exert a protective effect against non-alcoholic steatohepatitis. However, little is known about its role in the pathogenesis of obesity-induced renal injury. The aim of this study was to investigate the effects of metformin on high-fat diet (HFD)-induced kidney injury. Obesity was induced by HFD (60% of total calories from fat, 20% protein and 20% carbohydrates) in 6-week-old C57BL/6 mice. Mice were fed HFD plus 0.5% metformin. The effects of metformin on HFD-induced renal injury were evaluated by determining metabolic parameters, serum adipokine levels and renal AMPK/acetyl-CoA carboxylase (ACC) activities, as well as a histological examination. HFD induced metabolic derangement, systemic insulin resistance and glomerular mesangial matrix expansion. The administration of metformin reduced HFD-induced metabolic derangement and renal injury. The administration of metformin reduced the HFD-induced increase in adipokine expression and macrophage infiltration. Moreover, renal AMPK activity, which was decreased by HFD, was recovered following the administration of metformin; in addition, fatty acid oxidation was increased by the inhibition of ACC. These results indicate that metformin exerts beneficial effects on obesity-induced renal injury by regulating systemic inflammation, insulin resistance and the renal AMPK/ACC pathway. The clinical application of metformin to obese or early diabetic patients may be helpful in preventing obesity- or diabetes-related kidney disease.
代谢综合征的特征是胰岛素抵抗、血脂异常和高血压。这些代谢变化导致肥胖引起的肾脏损伤的发展。 AMP 激活的蛋白激酶 (AMPK) 是一种普遍存在的酶，参与细胞对代谢应激的代谢反应。二甲双胍是一种 AMPK 激活剂，据报道它对非酒精性脂肪性肝炎具有保护作用。然而，关于其在肥胖引起的肾脏损伤发病机制中的作用知之甚少。本研究旨在探讨二甲双胍对高脂肪饮食 (HFD) 诱导的肾脏损伤的影响。在 6 周龄 C57BL/6 小鼠中通过 HFD（总热量的 60%来自脂肪，20%来自蛋白质，20%来自碳水化合物）诱导肥胖。给予 HFD 加 0.5%二甲双胍。通过测定代谢参数、血清脂联素水平和肾脏 AMPK/乙酰辅酶 A 羧化酶 (ACC) 活性以及组织学检查来评估二甲双胍对 HFD 诱导的肾脏损伤的影响。HFD 引起代谢紊乱、全身胰岛素抵抗和肾小球系膜基质扩张。二甲双胍的给药减少了 HFD 诱导的代谢紊乱和肾脏损伤。二甲双胍的给药减少了 HFD 诱导的脂联素表达和巨噬细胞浸润增加。此外，HFD 降低的肾脏 AMPK 活性在给予二甲双胍后得到恢复；此外，ACC 的抑制增加了脂肪酸氧化。这些结果表明，二甲双胍通过调节全身炎症、胰岛素抵抗和肾脏 AMPK/ACC 途径对肥胖引起的肾脏损伤发挥有益作用。二甲双胍在肥胖或早期糖尿病患者中的临床应用可能有助于预防肥胖或糖尿病相关的肾脏疾病。
