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Journal of Traditional Chinese Medicine >

2025 , Vol. 45 >Issue 3: 528 - 537

DOI: https://doi.org/10.19852/j.cnki.jtcm.2025.03.009

Exploring the mechanism of Shenhua tablet (肾华片) alleviating renal injury by regulating macrophage glycolysis via hypoxia-inducible factor-1α/ pyruvate kinase M2 signaling pathway in diabetic kidney disease mice

  • Yuanchun CHEN ,
  • Jiaxing JING ,
  • Qingmin LI ,
  • Xiaohong ZHOU ,
  • Xiaofei JIN ,
  • Weijuan GAO ,
  • Xiangmei CHEN ,
  • Wentao YU
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  • 1 Graduate School, Hebei University of Chinese Medicine, Shijiazhuang 050091, China
    2 College of Acupuncture and Massage, Hebei University of Chinese Medicine, Shijiazhuang 050200, China
    3 College of Basic Medicine, Hebei University of Chinese Medicine, Shijiazhuang 050200, China
    4 Research Center, Hebei University of Chinese Medicine, Shijiazhuang 050200, China
    5 College of Basic Medicine, Hebei University of Chinese Medicine, Shijiazhuang 050200, China
    6 Hebei Key Laboratory of Chinese Medicine Research on Cardio-Cerebrovascular Diseases, Shijiazhuang 050091, China
    7 Department of Nephrology, First Medical Center of Chinese PLA General Hospital, Beijing 100853, China
    8 National Key Laboratory of Kidney Diseases, Beijing 100853, China; National Clinical Research Center for Kidney Diseases, Beijing 100853, China
    9 Beijing Key Laboratory of Kidney Disease Research, Beijing 100853, China
    10 College of Acupuncture and Massage, Hebei University of Chinese Medicine, Shijiazhuang 050200, China
    11 Hebei International Joint Research Center for Dominant Diseases in Chinese Medicine and Acupuncture, Shijiazhuang 050091, China
    12 Hebei Key Laboratory of Chinese Medicine Research on Cardio-Cerebrovascular Diseases, Shijiazhuang 050091, China

Received date: 2024-04-22

  Accepted date: 2024-08-29

  Online published: 2025-05-21

Supported by

National Natural Science Foundation of China: Basic Research on the Mechanism of Organ Immune Damage and the Diagnosis and Treatment of Integrated Traditional Chinese and Western Medicine(32141005)

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Abstract

OBJECTIVE: To investigate the impact of Shenhua tablet (肾华片, SHT) on renal macrophage polarization and renal injury in mice with diabetic kidney disease (DKD)and to explore the potential mechanism involving the hypoxia-inducible factor-1α (HIF-1α) and pyruvate kinase M2 (PKM2) signaling pathway, along with the glycolysis metabolism pathway.
METHODS: The animals were divided into the following groups: Model, Control, dapagliflozin, SHT low-dose, SHT medium-dose, and SHT high-dose. We assessed 24-hour urine protein (24 h-UTP) levels, urinary albumin-to-creatinine ratio, and regularly monitored fasting blood glucose during the treatment period. After treatment, we examined renal tissue structure, renal function (urea nitrogen, uric acid, creatinine, cystatin C, β2-microglobulin), and glycolysis in renal macrophages. Additionally, we observed macrophage polarization in renal tissue and measured inflammatory factors (tumor necrosis factor-α, interleukin-1β, interleukin-6, interleukin-10, monocyte chemoattractant protein-1) to assess the immunoinflammatory status of the renal tissue. Finally, we investigated the expression of the HIF-1α/ PKM2 signaling pathway in macrophages to explore its role in the glycolysis process.
RESULTS: SHT shows a beneficial effect in treating DKD by reducing 24 h-UTP, regulating blood glucose levels, improving renal tissue structure, protecting renal function, inhibiting macrophage glycolysis, reducing macrophage transformation to the M1 state, and suppressing the expression of the HIF-1α/PKM2 signaling pathway.
CONCLUSION: SHT may exert renoprotective effects by inhibiting macrophage glycolysis via the HIF-1α/PKM2 signaling pathway. This inhibition decreases macrophage M1 polarization and reduces immunoinflammatory injury in the renal tissue of DKD mice.

Key words： diabetic kidney disease; macrophages; glycolysis; hypoxia-inducible factor-1α; pyruvate kinase M2; Shenhua tablet

Cite this article

Yuanchun CHEN , Jiaxing JING , Qingmin LI , Xiaohong ZHOU , Xiaofei JIN , Weijuan GAO , Xiangmei CHEN , Wentao YU . Exploring the mechanism of Shenhua tablet (肾华片) alleviating renal injury by regulating macrophage glycolysis via hypoxia-inducible factor-1α/ pyruvate kinase M2 signaling pathway in diabetic kidney disease mice[J]. Journal of Traditional Chinese Medicine, 2025 , 45(3) : 528 -537 . DOI: 10.19852/j.cnki.jtcm.2025.03.009

References

1. Yao L, Liang X, Qiao Y, Chen BH, Wang P, Liu ZS. Mitochondrial dysfunction in diabetic tubulopathy. Metabolism 2022; 131: 155195.
2. Sinha SK, Nicholas SB. Pathomechanisms of diabetic kidney disease. J Clin Med 2023; 12: 7349.
3. Kong LY, Andrikopoulos S, Macisaac RJ, et al. Role of the adaptive immune system in diabetic kidney disease. J Diabetes Investig 2022; 13: 213-26.
4. Liu Y, Xu RY, Gu HY, et al. Metabolic reprogramming in macrophage responses. Biomark Res 2021; 9: 1.
5. Wang MD, Pang YY, Guo YF, et al. Metabolic reprogramming: a novel therapeutic target in diabetic kidney disease. Front Pharmacol 2022; 13: 970601.
6. Zhang XL, Li RK, Gao T, et al. Mechanism of ultrafiltration extract of angelicae sinensis radix and hedysari radix regulates HIF-1α signaling pathway mediated by renal hypoxia to ameliorate renal fibrosis in DKD rats. Zhong Guo Zhong Yao Za Zhi 2024; 49: 1602-10.
7. Li X, Ma TK, Wang M, et al. YY1-induced upregulation of LncRNA-ARAP1-AS2 and ARAP1 promotes diabetic kidney fibrosis via aberrant glycolysis associated with EGFR/PKM2/ HIF-1α pathway. Front Pharmacol 2023; 14: 1069348.
8. Mouton AJ, Li X, Hall ME, Hall JE. Obesity, hypertension, and cardiac dysfunction: novel roles of immunometabolism in macro-phage activation and inflammation. Circ Res 2020; 126: 789-806.
9. Chen XM, Chen J, Chen YP, et al. Multicentered randomized controlled clinical trial on patients with IgA nephropathy of Qi-Yin deficiency syndrome type. Zhong Guo Zhong Xi Yi Jie He Za Zhi 2007; 27: 101-5.
10. Geng WJ, Wei RB, Mao W, Liu XS, Shi SZ. Protective effects of compound Shenhua tablet on diabetic nephropathy rats. Zhong Guo Zhong Xi Yi Jie He Za Zhi 2012; 32: 352-5.
11. Li R, Shi CR, Wei CT, et al. Fufang Shenhua tablet inhibits renal fibrosis by inhibiting PI3K/AKT. Phytomedicine 2023; 116: 154873.
12. Li JJ, Chen XM, Gu Y, et al. Effect of compound Shenhua tablet on macrophage migration inhibition factor in renal tissue of 5/6 nephrectomized rats. Zhong Guo Zhong Xi Yi Jie He Za Zhi 2005; 25: 150-3.
13. Chen ZJ, Liu LJ, Gao CF, et al. Astragali Radix (Huangqi): a promising edible immunomodulatory herbal medicine. J Ethnopharmacol 2020; 258: 112895.
14. Li R, Shi CR, Wei CT, et al. Fufang shenhua tablet, Astragali Radix and its active component astragaloside IV: research progress on anti-inflammatory and immunomodulatory mechanisms in the kidney. Front Pharmacol 2023; 14: 1131635.
15. Chen DQ, Wu J, Li P. Therapeutic mechanism and clinical application of Chinese herbal medicine against diabetic kidney disease. Front Pharmacol 2022; 13: 1055296.
16. Yang Y, Wei RB, Zheng XY, et al. Effects of compound Shenhua tablet on renal tubular Na-+-K-+-ATPase in rats with acute ischemic reperfusion injury. Chin J Integr Med 2014; 20: 200-8.
17. He JY, Peng F, Chang JK, et al. The therapeutic effect of Shenhua tablet against mesangial cell proliferation and renal inflammation in mesangial proliferative glomerulonephritis. Biomed Pharmacother 2023; 165: 115233.
18. Cai A, Shen J, Yang X, et al. Dapagliflozin alleviates renal inflammation and protects against diabetic kidney diseases, both dependent and independent of blood glucose levels. Front Immunol 2023; 14: 1205834.
19. Jin SQ, Song Y, Zhou L, et al. Depletion of CUL4B in macrophages ameliorates diabetic kidney disease via miR-194-5p/ITGA9 axis. Cell Rep 2023; 42: 112550.
20. Qu DD, Lu J, Bi Y. Research progress of monocyte chemotactic protein-1 and type 2 diabetes mellitus. Yi Xue Zong Shu 2021; 27: 3896-900.
21. Li HQ, Liu N, Zheng ZY, Teng HL, Pei J. Clopidogrel delays and can reverse diabetic nephropathy pathogenesis in type 2 diabetic db/db mice. World J Diabetes 2022; 13: 600-12.
22. Gu CJ, Geng XW, Wu YC, et al. Engineered macrophage membrane-coated nanoparticles with enhanced CCR2 expression promote spinal cord injury repair by suppressing neuroinflammation and neuronal death. Small 2024; 20: e2305659.
23. Fang XH, Li ZJ, Liu CY, Mor G, Liao AH. Macrophage memory: types, mechanisms, and its role in health and disease. Immunology 2024; 171: 18-30.
24. Funes SC, Rios M, Escobar-Vera J, Kalergis AM. Implications of macrophage polarization in autoimmunity. Immunology 2018; 154: 186-95.
25. Youssef N, Noureldein MH, Riachi ME, Haddad A, Eid AA. Macrophage polarization and signaling in diabetic kidney disease: a catalyst for disease progression. Am J Physiol Renal Physiol 2024; 326: F301-12.
26. Zhang XL, Zhao Y, Zhu XD, et al. Active vitamin D regulates macrophage M1/M2 phenotypes via the STAT-1-TREM-1 pathway in diabetic nephropathy. J Cell Physiol 2019; 234: 6917-26.
27. Kolliniati O, Ieronymaki E, Vergadi E, Tsatsanis C. Metabolic regulation of macrophage activation. J Innate Immun 2022; 14: 51-68.
28. Wu HN, Lin CL, Huang CH. Research progress of glucose metabolism reprogramming in macrophage polarization. Zhong Guo Bing Li Sheng Li Za Zhi 2023; 39: 1650-7.
29. Liu J, Nie Y, Wang YY, Lian H. Research progress on macrophage metabolism and tissue repair. Xian Dai Mian Yi Xue 2022; 42: 248-53.
30. Wei XJ, Hou Y, Long MT, Jiang L, Du Y. Advances in energy metabolism in renal fibrosis. Life Sci 2023; 312: 121033.
31. Shirai T, Nazarewicz RR, Wallis BB, et al. The glycolytic enzyme PKM2 bridges metabolic and inflammatory dysfunction in coronary artery disease. J Exp Med 2016; 213:337-54.
32. Yang ZH, Wang BK, Li D, Gao S. Advances in energy metabolism and polarization of macrophages in myocardial infarction. Zhong Guo Mian Yi Xue Za Zhi 2023; 39: 2111-4.
33. Marrocco A, Ortiz LA. Role of metabolic reprogramming in pro-inflammatory cytokine secretion from LPS or silica-activated macrophages. Front Immunol 2022; 13: 936167.
34. Zhang BC, Zhang TT, Xiang CH, Liu YW. Luteolin regulates M1 macrophage polarization by inhibiting glycolytic pathway induced by HIF-α. Zhong Guo Yao Li Xue Tong Bao 2023; 39: 244-51.
35. Wu MM, Wang QM, Huang BY, et al. Dioscin ameliorates murine ulcerative colitis by regulating macrophage polarization. Pharmacol Res 2021; 172: 105796.
36. Zhao Y, Xing C, Deng YT, Ye C, Peng H. HIF-1α signaling: Essential roles in tumorigenesis and implications in targeted therapies. Genes Dis 2024; 11: 234-51.
37. Vatte S, Ugale R. HIF-1, an important regulator in potential new therapeutic approaches to ischemic stroke. Neurochem Int 2023; 170: 105605.
38. Yan YT, Yuan NN, Chen YC, et al. SKP alleviates the ferroptosis in diabetic kidney disease through suppression of HIF-1α/HO-1 pathway based on network pharmacology analysis and experimental validation. Chin Med 2024; 19: 31.
39. Zhou L, Zhao Y, Pan LC, et al. Sirolimus increases the anti-cancer effect of Huai Er by regulating hypoxia inducible factor-1α-mediated glycolysis in hepatocellular carcinoma. World J Gastroenterol 2022; 28: 4600-19.
40. Jia YJ, Chen JQ, Zheng ZK, et al. Tubular epithelial cell-derived extracellular vesicles induce macrophage glycolysis by stabilizing HIF-1α in diabetic kidney disease. Mol Med 2022; 28: 95.
41. Feng J, Li JJ, Wu LW, et al. Emerging roles and the regulation of aerobic glycolysis in hepatocellular carcinoma. J Exp Clin Cancer Res 2020; 39: 126.
42. Tu C, Wang LZ, WEI L. The role of PKM2 in diabetic microangiopathy. Diabetes Metab Syndr Obes 2022; 15: 1405-12.
43. Cramer T, Yamanishi Y, Clausen BE, et al. HIF-1alpha is essential for myeloid cell-mediated inflammation. Cell 2003; 112: 645-57.
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