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

doi:10.19852/j.cnki.jtcm.2025.03.009

Journal of Traditional Chinese Medicine ›› 2025, Vol. 45 ›› Issue (3): 528-537.DOI: 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

CHEN Yuanchun¹(), JING Jiaxing¹(), LI Qingmin², ZHOU Xiaohong³, JIN Xiaofei⁴, GAO Weijuan⁵^,⁶, CHEN Xiangmei⁷^,⁸^,⁹(), YU Wentao¹⁰^,¹¹^,¹²()

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:2024-04-22 Accepted:2024-08-29 Online:2025-06-15 Published:2025-05-21
Contact: Prof. YU Wentao, College of Acupuncture and Massage, Hebei University of Chinese Medicine, Shijiazhuang 050200, China. ywtawen@163.com; Academician. CHEN Xiangmei, Department of Nephrology, First Medical Center of Chinese PLA General Hospital, Beijing 100853, China. xmchen301@126.com,Telephone: +86-18229967100
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)

1. .pdf(459KB)

Abstract

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

CHEN Yuanchun, JING Jiaxing, LI Qingmin, ZHOU Xiaohong, JIN Xiaofei, GAO Weijuan, CHEN Xiangmei, YU Wentao. 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.

Figures/Tables 8

Table 1 Effects of SHT on FBG of DKD mice ($\bar{x}±s$)

Group	n	Dose (g/kg)	FBG (mmol/L)
Group	n	Dose (g/kg)	12W	14W	16W	18W	20W
Control	6	-	9.9±1.4	11.3±1.3	11.1±1.6	10.4±0.8	10.6±0.7
Model	6	-	25.3±4.6^a	28.0±4.1^a	27.9±3.6^a	29.8±3.2^a	30.9±2.1^a
DAPA	6	0.001	26.0±5.1^a	15.0±1.1^b	12.2±2.1^b	12.0±2.0^b	12.1±1.6^b
SHT-H	6	1.8	25.7±4.0^a	25.7±5.3	25.8±2.9	25.7±1.4^b	24.2±1.3^b
SHT-M	6	0.9	25.1±3.7^a	27.1±3.4	26.8±2.8	27.5±2.9	28.3±2.5^c
SHT-L	6	0.45	25.5±4.2^a	27.9±3.3	27.3±3.4	29.3±3.7	29.7±2.1

Table 2 Effects of SHT on 24 h-UTP and UACR of DKD mice ($\bar{x}±s$)

Group	n	Dose (g/kg)	24 h-UTP (mg)		UACR (mg/mmol)
Group	n	Dose (g/kg)	12 W	20 W	12 W	20 W
Control	6	-	0.30±0.05	1.29±0.14	72.21±9.36	85.22±10.56
Model	6	-	1.20±0.19^a	8.52±0.63^a	120.41±12.59^a	614.41±30.54^a
DAPA	6	0.001	1.26±0.22^a	6.58±0.78^b	114.88±9.15^a	374.44±40.36^b
SHT-H	6	1.8	1.30±0.22^a	7.29±0.46^b	122.21±21.86^a	404.96±17.69^b
SHT-M	6	0.9	1.25±0.17^a	7.62±0.65^b	120.76±20.12^a	415.87±26.27^b
SHT-L	6	0.45	1.22±0.20^a	7.79±0.47^c	113.59±12.50^a	465.87±35.59^b

Figure 1 SHT attenuated renal injury in DKD mice A: HE staining of kidney tissue (× 200, scale bar = 100 μm, n = 3); A1: Control group; A2: Model group; A3: DAPA group; A4: SHT-H group; A5: SHT-M group; A6: SHT-L group. B: PAS staining of kidney tissue (× 200, scale bar = 100 μm, n = 3); B1: Control group; B2: Model group; B3: DAPA group; B4: SHT-H group; B5: SHT-M group; B6: SHT-L group. In HE staining, black arrows indicate loose and light-stained cytoplasm, blue arrows indicate lymphocyte infiltration, and red arrows indicate renal tubular necrosis. In PAS staining, black arrows indicate an increased mesangial matrix. DAPA group (dapagliflozin oral administration, 1 mg/kg per day, 8 weeks), SHT-L group (SHT oral administration, 0.45 g/kg per day, 8 weeks), SHT-M group (SHT oral administration, 0.9 g/kg per day, 8 weeks), and SHT-H group (SHT oral administration, 1.8 g/kg per day, 8 weeks), control and model groups were given normal saline (0.1 mL/10 g per day, 8 weeks). SHT: Shenhua tablet; DKD: diabetic kidney disease; HE: hematoxylin-eosin; DAPA: dapagliflozin; SHT-H: Shenhua tablet high-dose; SHT-M: Shenhua tablet medium-dose; SHT-L: Shenhua tablet low-dose; PAS: periodic acid Schiff’s.

Table 3 Effects of SHT on BUN, UA, Scr, Cys C, and β2-MG in the serum of DKD mice ($\bar{x}±s$)

Group	n	Dose (g/kg)	BUN (mmol/L)	Scr (μmol/L)	UA (μmol/L)	β2-MG (μg/L)	Cys C (mg/L)
Control	6	-	5.75±0.40	16.09±0.95	119.78±11.49	79.97±4.84	2.25±0.12
Model	6	-	10.15±0.60^a	36.62±2.17^a	231.82±16.17^a	148.07±7.93^a	3.10±0.32^a
DAPA	6	0.001	6.78±0.76^b	21.93±1.48^b	189.81±13.76^b	107.05±9.13^b	2.58±0.23^b
SHT-H	6	1.8	8.00±0.48^b	25.84±1.42^b	195.48±16.06^b	117.86±7.65^b	2.64±0.20^b
SHT-M	6	0.9	8.51±0.64^b	32.64±2.11^b	209.70±8.14^b	127.49±10.39^b	2.67±0.23^b
SHT-L	6	0.45	9.36±0.37^c	34.21±1.56^c	215.66±6.96^c	135.90±9.97^c	2.78±0.19^c

Figure 2 SHT inhibits macrophage polarization toward the M1 type A: expression of M1 macrophage marker (CD86, green) was examined by immunofluorescence staining, and nuclei were stained with DAPI (blue) (× 400, scale bar = 20 μm, n = 3); A1-A3: Control group; A4-A6: Model group; A7-A9: DAPA group; A10-A12: SHT-H group; A13-A15: SHT-M group; A16-A18: SHT-L group; B: expression of M2 macrophage marker (CD206, green) was examined by immunofluorescence staining, and nuclei were stained with DAPI (blue) (× 400, scale bar = 20 μm, n = 3); B1-B3: control group; B4-B6: model group; B7-B9: DAPA group; B10-B12: SHT-H group; B13-B15: SHT-M group; B16-B18: SHT-L group; C: relative fluorescence intensity of CD86 was determined using ImageJ software; D: relative fluorescence intensity of CD206 was determined using ImageJ software. DAPA group (dapagliflozin oral administration, 1 mg/kg per day, 8 weeks), SHT-L group (SHT oral administration, 0.45 g/kg per day, 8 weeks), SHT-M group (SHT oral administration, 0.9 g/kg per day, 8 weeks), and SHT-H group (SHT oral administration, 1.8 g/kg per day, 8 weeks), control and model groups were given normal saline (0.1 mL/10 g per day, 8 weeks). SHT: Shenhua tablet; DAPI: 4',6-diamidino-2-phenylindole; DAPA: dapagliflozin; SHT-H: Shenhua tablet high-dose; SHT-M: Shenhua tablet medium-dose; SHT-L: Shenhua tablet low-dose. Statistical analyses were measured using a one-way analysis of variance for multiple comparisons. Data were presented as mean ± standard deviation. aP < 0.01 vs control group; bP < 0.01, cP < 0.05 vs model group.

Table 4 Effects of SHT on the levels of TNF-α, IL-1β, IL-6, MCP-1, and IL-10 in kidney tissue of DKD mice ($\bar{x}±s$)

Group	n	Dose (g/kg)	TNF-α (pg/mL)	IL-1β (pg/mL)	IL-6 (pg/mL)	MCP-1 (pg/mL)	IL-10 (pg/mL)
Control	6	-	32±6	30±5	71±6	844±71	458±35
Model	6	-	111±4^a	58±6^a	202±13^a	2068±181^a	118±11^a
DAPA	6	0.001	73±4^b	43±5^b	170±11^b	1419±111^b	311±24^b
SHT-H	6	1.8	92±8^b	48±4^b	176±8^b	1318±193^b	288±23^b
SHT-M	6	0.9	96±9^b	49±5^b	178±9^b	1546±181^b	219±23^b
SHT-L	6	0.45	97±9^b	52±5^c	182±13^b	1674±122^b	160±15^b

Figure 3 Effect of SHT on regulating glycolysis in macrophages A: expression of HK1 in macrophages was observed by staining the glycolysis rate-limiting enzyme HK1 (green) and the macrophage marker F4/80 (red) with two-color immunofluorescence, and nuclei were stained with DAPI (blue), (× 400, scale bar = 20 μm, n = 3); A1-A4: control group; A5-A8: model group; A9-A12: DAPA group; A13-A16: SHT-H group; A17-A20: SHT-M group; A21-A24: SHT-L group. B: expression of LDHA in macrophages was observed by staining LDHA (green) and the macrophage marker F4/80 (red) with two-color immunofluorescence, and nuclei were stained with DAPI (blue), (× 400, scale bar, 20 μm, n = 3); B1-B4: control group; B5-B8: model group; B9-B12: DAPA group; B13-B16: SHT-H group; B17-B20: SHT-M group; B21-B24: SHT-L group. The last column of the composite picture shows a magnified view of a section of the merge picture. DAPA group (dapagliflozin oral administration, 1 mg/kg per day, 8 weeks), SHT-L group (SHT oral administration, 0.45 g/kg per day, 8 weeks), SHT-M group (SHT oral administration, 0.9 g/kg per day, 8 weeks), and SHT-H group (SHT oral administration, 1.8 g/kg per day, 8 weeks), Control and Model groups were given normal saline (0.1 mL/10 g per day, 8 weeks). SHT: Shenhua tablet; HK1: hexokinase 1; DAPI: 4',6-diamidino-2-phenylindole; DAPA: dapagliflozin; SHT-H: Shenhua tablet high-dose; SHT-M: Shenhua tablet medium-dose; SHT-L: Shenhua tablet low-dose; LDHA: lactate dehydrogenase A.

Figure 4 Regulatory effect of SHT on the HIF-1α/PKM2 signaling pathway in macrophages A: expression of HIF-1α in macrophages was observed by staining HIF-1α (green) and the macrophage marker F4/80 (red) using two-color immunofluorescence, with nuclei stained using DAPI (blue), (× 400, scale bar = 20 μm, n = 3); A1-A4: control group; A5-A8: model group; A9-A12: DAPA group; A13-A16: SHT-H group; A17-A20: SHT-M group; A21-A24: SHT-L group. B: expression of PKM2 in macrophages was observed by staining PKM2 (green) and the macrophage marker F4/80 (red) using two-color immunofluorescence, with nuclei stained using DAPI (blue), (× 400, scale bar = 20 μm, n = 3); B1-B4: control group; B5-B8: model group; B9-B12: DAPA group; B13-B16: SHT-H group; B17-B20: SHT-M group; B21-B24: SHT-L group. The last column of the composite picture shows a magnified view of a section of the merge picture. DAPA group (dapagliflozin oral administration, 1 mg/kg per day, 8 weeks), SHT-L group (SHT oral administration, 0.45 g/kg per day, 8 weeks), SHT-M group (SHT oral administration, 0.9 g/kg per day, 8 weeks), and SHT-H group (SHT oral administration, 1.8 g/kg per day, 8 weeks), control and model groups were given normal saline (0.1 mL/10 g per day, 8 weeks). SHT: Shenhua tablet; HIF-1α：hypoxia-inducible factor-1α; PKM2: pyruvate kinase M2; DAPI: 4',6-diamidino-2-phenylindole; DAPA: dapagliflozin; SHT-H: Shenhua tablet high-dose; SHT-M: Shenhua tablet medium-dose; SHT-L: Shenhua tablet low-dose.

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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

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