Shen Shuai II Recipe inhibits hypoxia-induced glycolysis by preserving mitochondrial dynamics to attenuate kidney fibrosis

Lingchen Wang; Xiaoxuan Feng; Chaoyang Ye; Chen Wang; Meng Wang

doi:10.1016/j.jep.2023.116271

Shen Shuai II Recipe inhibits hypoxia-induced glycolysis by preserving mitochondrial dynamics to attenuate kidney fibrosis

J Ethnopharmacol. 2023 May 23:308:116271. doi: 10.1016/j.jep.2023.116271. Epub 2023 Feb 15.

Authors

Lingchen Wang¹, Xiaoxuan Feng², Chaoyang Ye³, Chen Wang⁴, Meng Wang⁵

Affiliations

¹ 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. Electronic address: wlc309415@163.com.
² 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. Electronic address: 583665001@qq.com.
³ 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. Electronic address: yechaoyang63@126.com.
⁴ 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. Electronic address: chenwang42@126.com.
⁵ 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. Electronic address: twsa927101@163.com.

PMID: 36806483
DOI: 10.1016/j.jep.2023.116271

Abstract

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.

Keywords: Crosstalk; Glycolysis; Hypoxic kidney injury; Mitochondria; Traditional Chinese medicine.

MeSH terms

Animals
Fibrosis
Glycolysis
Hypoxia / metabolism
Kidney
Kidney Diseases* / drug therapy
Mitochondrial Dynamics
Rats
Renal Insufficiency, Chronic* / drug therapy