二甲双胍通过激活AMPK/PPARα通路减轻肥胖胰岛素抵抗大鼠的肾功能障碍

IF 6.9 3区 医学 Q1 CHEMISTRY, MEDICINAL
Laongdao Thongnak, Nattavadee Pengrattanachot, Sasivimon Promsan, Nichakorn Phengpol, Prempree Sutthasupha, Krit Jaikumkao, Anusorn Lungkaphin
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引用次数: 0

摘要

胰岛素信号和脂质代谢被长期高脂肪饮食(HFD)所破坏。由于amp活化的蛋白激酶(AMPK)和过氧化物酶体增殖物活化受体-α (PPARα)或AMPK/PPARα途径失活,这种破坏可导致胰岛素抵抗、血脂异常和随后的肾功能障碍。在HFD诱导的胰岛素抵抗大鼠中,我们研究了二甲双胍通过调节ampk调节的ppar α依赖通路来预防肾功能障碍的影响。雄性Wistar大鼠喂HFD 16周诱导胰岛素抵抗。确诊胰岛素抵抗后,给予二甲双胍(30mg /kg)或吉非齐尔(50mg /kg)口服8周。在HF大鼠中观察到胰岛素抵抗、血脂异常、脂质积累和肾损伤的证据。心衰大鼠的脂质氧化、能量代谢和肾有机阴离子转运蛋白3 (Oat3)的表达和功能受到损害。二甲双胍可以刺激AMPK/PPARα通路,抑制甾醇调节元件结合转录因子1 (SREBP1)和脂肪酸合成酶(FAS)信号通路(SREBP1/FAS),从而调控脂质代谢。二甲双胍治疗比吉非齐治疗更有效地降低了HFD诱导的肾脏炎症标志物和肾纤维化表达。有趣的是,在二甲双胍和吉非齐治疗后,肾脏Oat3功能和表达以及肾损伤得到改善。在二甲双胍或吉非齐治疗后,肾分化簇36 (CD36)或葡萄糖钠共转运蛋白2型(SGLT2)的表达没有差异。二甲双胍和吉非齐尔可以通过AMPK/ ppar α依赖途径减轻HFD诱导的肥胖肾损伤的损害。有趣的是,通过ampk调控的SREBP1/FAS信号通路,二甲双胍在减轻肾脂毒性方面比吉非罗吉更有效。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Metformin mitigates renal dysfunction in obese insulin-resistant rats via activation of the AMPK/PPARα pathway

Metformin mitigates renal dysfunction in obese insulin-resistant rats via activation of the AMPK/PPARα pathway

Insulin signaling and lipid metabolism are disrupted by long-term consumption of a high-fat diet (HFD). This disruption can lead to insulin resistance, dyslipidemia and subsequently renal dysfunction as a consequence of the inactivation of the AMP-activated protein kinase (AMPK) and peroxisome proliferator-activated receptor-α (PPARα) or AMPK/PPARα pathways. We investigated the impact of metformin on the prevention of renal dysfunction through the modulation of AMPK-regulated PPARα-dependent pathways in insulin-resistant rats induced by a HFD. Male Wistar rats were fed a HFD for 16 weeks to induce insulin resistance. After insulin resistance had been confirmed, metformin (30 mg/kg) or gemfibrozil (50 mg/kg) was given orally for 8 weeks. Evidence of insulin resistance, dyslipidemia, lipid accumulation and kidney injury were observed in HF rats. Impairment of lipid oxidation, energy metabolism and renal organic anion transporter 3 (Oat3) expression and function were demonstrated in HF rats. Metformin can stimulate the AMPK/PPARα pathways and suppress sterol regulatory element-binding transcription factor 1 (SREBP1) and fatty acid synthase (FAS) signaling (SREBP1/FAS) to enable the regulation of lipid metabolism. Renal inflammatory markers and renal fibrosis expression induced by a HFD were more effectively reduced after metformin treatment than after gemfibrozil treatment. Interestingly, renal Oat3 function and expression and kidney injury were improved following metformin and gemfibrozil treatment. Renal cluster of differentiation 36 (CD36) or sodium glucose cotransporter type 2 (SGLT2) expression did not differ after treatment with metformin or gemfibrozil. Metformin and gemfibrozil could reduce the impairment of renal injury in obese conditions induced by a HFD through the AMPK/PPARα-dependent pathway. Interestingly, metformin demonstrated greater efficacy than gemfibrozil in attenuating renal lipotoxicity through the AMPK-regulated SREBP1/FAS signaling pathway.

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来源期刊
CiteScore
13.40
自引率
9.00%
发文量
48
审稿时长
3.3 months
期刊介绍: Archives of Pharmacal Research is the official journal of the Pharmaceutical Society of Korea and has been published since 1976. Archives of Pharmacal Research is an interdisciplinary journal devoted to the publication of original scientific research papers and reviews in the fields of drug discovery, drug development, and drug actions with a view to providing fundamental and novel information on drugs and drug candidates.
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