沈氏帅 II 方通过维持线粒体动态平衡抑制缺氧诱导的糖酵解来减轻肾脏纤维化。
Shen Shuai II Recipe inhibits hypoxia-induced glycolysis by preserving mitochondrial dynamics to attenuate kidney fibrosis.
机构信息
Department of Nephrology, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, PR China; Key Laboratory of Liver and Kidney Diseases, Ministry of Education, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, PR China; TCM Institute of Kidney Disease, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, PR China; Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, PR China.
出版信息
J Ethnopharmacol. 2023 May 23;308:116271. doi: 10.1016/j.jep.2023.116271. Epub 2023 Feb 15.
ETHNOPHARMACOLOGICAL RELEVANCE
Shen Shuai II Recipe (SSR) is a traditional Chinese medicine prescription with significant clinical efficacy in chronic kidney disease (CKD) by invigorating Qi and resolving blood stasis, clearing away heat and dampness. Our previous studies demonstrated that SSR attenuated renal interstitial fibrosis (RIF) by improving hypoxia and mitochondrial dysfunction.
AIM OF THE STUDY
The aim of this study was to investigate the potential mechanisms of SSR against RIF.
MATERIALS AND METHODS
The CKD was established by 5/6 ablation/infarction (A/I) operation. After 4 weeks, rats were gavaged with SSR or Fenofibrate for 8 weeks. Hypoxia-treated NRK-52 E cells were treated with SSR and (or) glycolysis inhibitors, including GSK2837808 A (GSK) and 2-Deoxy-D-glucose (2-DG). In addition, Drp1-deficient or MFP-M1-treated NRK-52 E cells were treated with SSR under hypoxic conditions. The effects of SSR on fibrotic phenotype, glycolysis, mitochondrial dynamics and membrane potential in hypoxia-exposed NRK-52 E cells were examined by immunoblotting, colorimetric, and fluorometric methods. Furthermore, we constructed a lactic acid-induced activation model of NRK-49 F cells and a co-culture system. The activation of NRK-49 F cells was evaluated by immunoblotting method.
RESULTS
Our findings indicated that SSR significantly attenuated abnormal glycolysis in vivo and in vitro, which was correlated with its renoprotective effect. Further studies revealed that improvement of mitochondrial dynamics could be one of the mechanisms by which SSR inhibits glycolysis to achieve anti-renal fibrosis. Furthermore, treatment with SSR significantly inhibited the lactic acid-induced activation of NRK-49 F cells. The co-culture results further highlighted that SSR inhibited activation of renal fibroblasts and deposition of extracellular matrix by reducing glycolysis in renal tubular cells.
CONCLUSIONS
SSR alleviates RIF by inhibiting hypoxia-induced glycolysis through improvement of mitochondrial dynamics.
民族药理学相关性
参芍 II 方（SSR）是一种中药方剂，具有益气活血、清热利湿的显著临床疗效，可治疗慢性肾脏病（CKD）。我们之前的研究表明，SSR 通过改善缺氧和线粒体功能障碍来减轻肾间质纤维化（RIF）。
研究目的
本研究旨在探讨 SSR 防治 RIF 的潜在机制。
材料与方法
采用 5/6 切除/梗死（A/I）手术建立 CKD 模型。4 周后，大鼠给予 SSR 或非诺贝特灌胃 8 周。将缺氧处理的 NRK-52E 细胞用 SSR 和（或）糖酵解抑制剂（GSK2837808A 和 2-脱氧-D-葡萄糖（2-DG））处理。此外，在缺氧条件下，用 Drp1 缺陷或 MFP-M1 处理的 NRK-52E 细胞用 SSR 处理。通过免疫印迹、比色法和荧光法检测 SSR 对缺氧暴露的 NRK-52E 细胞中纤维化表型、糖酵解、线粒体动力学和膜电位的影响。此外，我们构建了乳酸诱导的 NRK-49F 细胞激活模型和共培养系统。通过免疫印迹法评估 NRK-49F 细胞的激活情况。
结果
我们的研究结果表明，SSR 可显著减轻体内和体外异常糖酵解，这与其肾脏保护作用相关。进一步的研究表明，改善线粒体动力学可能是 SSR 抑制糖酵解以实现抗肾纤维化的机制之一。此外，SSR 治疗可显著抑制乳酸诱导的 NRK-49F 细胞激活。共培养结果进一步强调，SSR 通过降低肾小管细胞的糖酵解来抑制肾成纤维细胞的激活和细胞外基质的沉积。
结论
SSR 通过改善线粒体动力学抑制缺氧诱导的糖酵解来减轻 RIF。
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