Yishen Tongluo formula (益肾通络方) ameliorates kidney injury via modulating inflammation and apoptosis in streptozotocin-induced diabetic kidney disease mice

doi:10.19852/j.cnki.jtcm.2025.02.007

Journal of Traditional Chinese Medicine ›› 2025, Vol. 45 ›› Issue (2): 254-265.DOI: 10.19852/j.cnki.jtcm.2025.02.007

• Original articles • Previous Articles Next Articles

Yishen Tongluo formula (益肾通络方) ameliorates kidney injury via modulating inflammation and apoptosis in streptozotocin-induced diabetic kidney disease mice

YUAN Jiayao¹, WU Suhui¹, MENG Yufan², LI Hanbing¹, LI Genlin¹(), XU Jiangyan³()

1 Clinical Pharmacology Teaching and Research Office, School of Medicine, Henan University of Chinese Medicine, Zhengzhou 450000, China
2 School of Pharmacolog, Henan Medical College, Zhengzhou 450000, China
3 Academy of Chinese Medical Sciences, Henan University of Chinese Medicine, Zhengzhou 450000, China

Received:2024-03-23 Accepted:2024-11-29 Online:2025-04-15 Published:2025-03-10
Contact: Pro. LI Genlin, Clinical Pharmacology Teaching and Research Office, School of Medicine, Henan University of Chinese Medicine, Zhengzhou 450000, China. lgl88@hactcm.edu.cn; Pro. XU Jiangyan, Academy of Chinese Medical Sciences, Henan University of Chinese Medicine, Zhengzhou 450000, China. xujiangyan2008@163.com, Telephone: +86-371-65934070
About author:YUAN Jiayao and WU Suhui are co-first authors and contributed equally to this work
Supported by:
National Key Research and Development Plan: Evidence-Based Evaluation and Therapeutic Mechanism Cooperation Study of Yishen Tongluo Formula for Preventing Diabetes Kidney Disease (Phase 3)(2020YFE0201800);Key Science and Technology Projects of Henan Province: Research on Innovative Drug Cooperation of Traditional Chinese Medicine Yishen Tongluo Concentrated Pills (益肾通络浓缩丸)(221111520300);National Natural Science Foundation of China: the Mechanism of Yishen Tongluo Formula Intervention in Diabetic Kidney Disease based on (Yin-Yang-1/Nuclear Factor Erythroid 2-Related Factor 2 Mediated Endothelial Podocyte Interaction Response (No. 82474495) to XU Jiangyan;Key scientific and technological projects of Henan province: Study on the Pharmacodynamic Mechanism of Yishen Tongluo Formula in Treatment of Diabetes Kidney Disease based on the Interaction Regulation of Protein Phosphorylation and Acylation Modification (No. 212102310347) to WU Suhui

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Abstract

Abstract:

OBJECTIVE: To investigate the effect and mechanism of Yishen Tongluo formula (益肾通络方, YSTLF) in streptozotocin-induced diabetic kidney disease mice (DKD) mice.

METHODS: Thirty Institute of Cancer Research mice (specific pathogen free, SPF grade) were divided into five groups (n = 6 per group): control, DKD model, DKD model with YSTLF (4.9 g/kg), DKD model with YSTLF (9.8 g/kg), and DKD model with captopril. DKD was induced through a single intraperitoneal injection of streptozotocin (150 mg/kg). Body weight, fasting blood glucose and urine C-peptide levels were measured to assess metabolic regulation by YSTLF. Renal function was evaluated using indicators of glomerular and tubular health. Liver function was assessed by measuring aspartate aminotransferase and alanine aminotransferase levels. Renal pathological changes were examined using hematoxylin/eosin staining and transmission electron microscopy. Inflammatory and apoptosis-related factors were analyzed through enzyme-linked immunosorbent assay, immunohistochemistry, and Western blot analysis.

RESULTS: In DKD mice, fasting blood glucose, C-peptide, 24-hour urine protein (UP) levels, and renal damage were elevated, accompanied by increased inflammation and apoptosis. YSTLF significantly reduced 24-hour UP and C-peptide levels and improved kidney and liver function in DKD mice. YSTLF also mitigated glomerular hypertrophy, basement membrane thickening, and podocyte foot process effacement. It upregulated the expression of the podocyte marker podocalyxin. Furthermore, YSTLF alleviated inflammation and apoptosis, likely by reducing the overexpression of monocyte chemoattractant protein (MCP-1), Bax, and Caspase-3 in the kidneys of DKD mice.

CONCLUSIONS: These findings suggest that YSTLF ameliorates kidney injury by modulating the expression of inflammatory cytokine MCP-1 and the Bax/Caspase-3 apoptosis pathway, providing a potential therapeutic approach for DKD.

Key words: diabetic nephropathies, inflammation, apoptosis, Yishen Tongluo formula

YUAN Jiayao, WU Suhui, MENG Yufan, LI Hanbing, LI Genlin, XU Jiangyan. Yishen Tongluo formula (益肾通络方) ameliorates kidney injury via modulating inflammation and apoptosis in streptozotocin-induced diabetic kidney disease mice[J]. Journal of Traditional Chinese Medicine, 2025, 45(2): 254-265.

Figures/Tables 9

Figure 1 Chromatogram of YSTLF A: mixed standard; B: YSTLF. 1: Monoside; 2: Loganin; 3: Campanulin; 4: Acetoside; 5: Salvianolic acid B; 6: Aloemodin; 7: Rhein; 8: Cryptotanshinone; 9: Chrysophanol; 10: Danshinone I; 11: Emodin Methyl Ether; 12: Danshinone ⅡA. YSTLF: Yishen Tongluo formula.

Table 1 YSTLF has little effect on the body weight and kidney weight of DKD mice ($\bar{x}±s$)

Group	n	Body mass (g)			Kidney weight (g)	Kidney index (%)
Group	n	0 week	4 weeks	7 weeks	Kidney weight (g)	Kidney index (%)
CON	6	46.40±2.47	45.52±3.27	46.85±3.93	0.69±0.09	1.78±0.31
MOD	6	33.05±4.50^a	39.57±3.20^a	39.67±4.91^a	0.87±0.06^a	2.61±0.27^a
YSTLF 4.9 g/kg	6	34.40±6.27	37.60±3.88	37.02±3.45	0.86±0.16	2.57±0.06
YSTLF 9.8 g/kg	6	35.25±3.07	41.23±5.54	39.20±4.20	0.85±0.07	2.53±0.41
CTP	6	37.55±6.10	42.48±6.10	41.98±6.81	0.85±0.11	2.20±0.46

Table 2 YSTLF has an effect on FBG and urine C-peptide levels of the DKD mice ($\bar{x}±s$)

Group	n	FBG (mmol/L)				Urine C-Peptide (ng/mL)
Group	n	0 week	2 weeks	4 weeks	7 weeks	Urine C-Peptide (ng/mL)
CON	6	7.850±1.581	8.683±1.566	7.717±1.686	7.117±1.652	0.054±0.009
MOD	6	31.100±2.798^a	31.600±1.920^a	28.467±4.198^a	30.367±3.402^a	0.462±0.127^a
YSTLF 4.9 g/kg	6	31.150±3.026	30.951±4.303	30.483±3.731	27.750±5.665	0.329±0.042^b
YSTLF 9.8 g/kg	6	31.017±2.573	28.183±6.751	25.400±5.322	23.717±5.338	0.235±0.036^b
CTP	6	31.325±3.950	31.202±4.200	30.825±4.752	25.525±5.055	0.244±0.033^b

Table 3 YSTLF reduced the urine protein content and improved the renal function of DKD mice ($\bar{x}±s$)

Group	n	24-h urine protein (mg/24h)			β2-MG (mg/L)	BUN (mmol/L)	UA (μmol/L)	LDH (U/L)
Group	n	0 week	4 weeks	7 weeks	β2-MG (mg/L)	BUN (mmol/L)	UA (μmol/L)	LDH (U/L)
CON	6	2.007±0.820	1.713±0.735	1.688±0.315	0.180±0.013	2.677±0.577	59.798±16.054	414.457±42.373
MOD	6	3.978±0.678^a	5.762±1.066^a	7.363±1.466^a	0.232±0.008^a	4.343±0.740^a	106.667±11.778^a	480.322±27.629^a
YSTLF 4.9 g/kg	6	3.843±0.779	5.328±1.523	4.518±1.226^c	0.200±0.009^b	2.384±0.588^b	68.364±13.100^b	403.372±62.011^b
YSTLF 9.8 g/kg	6	4.035±0.987	4.967±2.029	3.657±1.037^b	0.212±0.008^b	3.363±0.512^c	64.647±16.632^b	418.073±26.474^c
CTP	6	3.832±1.103	5.625±2.825	4.665±1.316	0.190±0.08^b	2.983±0.609^b	64.243±10.749^b	406.025±23.970^b

Table 4 YSTLF promoted liver function of the DKD mice (U/L, $\bar{x}±s$)

Group	n	AST	ALT
CON	6	5.44±1.31	6.59±1.36
MOD	6	12.52±1.35^a	19.35±2.79^a
YSTLF 4.9 g/kg	6	8.11±1.56^b	9.79±1.64^b
YSTLF 9.8 g/kg	6	9.09±1.50^b	10.79±2.65^b
CTP	6	9.95±0.74^b	12.85±1.71^b

Figure 2 YSTLF ameliorated renal injury of the DKD mice A: representative HE staining images (× 400, scale bar = 50 μm) of renal corpuscles and tubules. The black arrow indicates thickened glomerular basement membrane, the yellow arrow indicates mesangial matrix expansion, and the white arrow indicates renal capsule shrinkage and adhesion. A1: CON group, A2: MOD group, A3: YSTLF 4.9 g/kg group, A4: YSTLF 9.8 g/kg group, A5: CTP group. B: glomerular diameters. CON group: drink and eat freely + an equal volume of citrate buffer with model group by intraperitoneal injection + the same volume of pure water was given by gavage; MOD group: with 150 mg/kg STZ dissolved in citrate buffer to induce DKD by intraperitoneal injected. YSTLF 4.9 g/kg group: model group + YSTLF 4.9 g/kg per day; YSTLF 9.8 g/k group: model group + YSTLF 9.8 g/kg per day; CTP group: model group + CTP 12.5 mg/kg per day. DKD: diabetic kidney disease mice; CON: Control group; MOD: Model group; YSTLF: Yishen Tongluo formula; CTP: Captopril group. Statistical analyses were measured using a one-way analysis of variance for multiple comparisons. Data were presented as mean ± standard deviation (n = 6). Compared with the control group, aP < 0.01; compared with the model group, bP < 0.01, cP < 0.05.

Figure 3 YSTLF alleviated glomerulus injury of the DKD mice A: representative electron micrograph images (× 5000, scale bar = 2 μm) of the glomerulus. The black line indicates GBM, the red arrow indicates normal foot processes, and the yellow arrow indicates fused foot processes, A1: CON group, A2: MOD group, A3: YSTLF 4.9 g/kg group, A4: YSTLF 9.8 g/kg group, A5: CTP group. B: TGBM. CON group: drink and eat freely + an equal volume of citrate buffer with model group by intraperitoneal injection + the same volume of pure water was given by gavage; MOD group: with 150 mg/kg STZ dissolved in citrate buffer to induce DKD by intraperitoneal injected. YSTLF 4.9 g/kg group: model group + YSTLF 4.9 g/kg per day; YSTLF 9.8 g/k group: model group + YSTLF 9.8 g/kg per day; CTP group: model group + CTP 12.5 mg/kg per day. DKD: diabetic kidney disease mice; CON: Control group; MOD: Model group; YSTLF: Yishen Tongluo formula; CTP: Captopril group; TGBM: the mean GBM thickness. Statistical analyses were measured using a one-way analysis of variance for multiple comparisons. Data were presented as mean ± standard deviation (n = 6). Compared with the control group, aP < 0.01; compared with the model group, bP < 0.01.

Table 5 YSTLF downregulated inflammation to improve the glomerular and podocyte injury in the DKD mice ($\bar{x}±s$)

Group	n	PCX (ng/mL)	MCP-1 (pg/mL)
CON	6	11.58±0.55	15.60±1.01
MOD	6	6.94±0.14^a	34.03±1.30^a
YSTLF 4.9 g/kg	6	7.61±0.60^b	23.16±0.38^b
YSTLF 9.8 g/kg	6	10.62±0.25^b	21.87±0.96^b
CTP	6	7.61±0.80^b	21.07±1.91^b

Figure 4 YSTLF attenuated kidney apoptosis in DKD mice A: Bax protein expression in renal tissue; B: Bax expression in renal tubules; C: Caspase-3 expression in renal interstitials as determined by immunohistochemistry (×400, scale bar = 20 μm); D: Bax and Caspase-3 protein expression in renal tissue assessed by Western blot. A1, B1, C1: CON group, A2, B2, C2: MOD group, A3, B3, C3: YSTLF 4.9 g/kg group, A4, B4, C4: YSTLF 9.8 g/kg group, A5, B5, C5: CTP group. A6: Average optical density of Bax; B6: Average optical density of Caspase-3 in renal tubules; C6: Average optical density of Caspase-3 in renal interstitial. D1: representative band of Bax and Caspase-3 protein detected by WB; D2: relative protein levels of Bax results; D3: relative protein levels of Caspase-3 results. CON group: drink and eat freely + an equal volume of citrate buffer with model group by intraperitoneal injection + the same volume of pure water was given by gavage; MOD group: with 150 mg/kg STZ dissolved in citrate buffer to induce DKD by intraperitoneal injected. YSTLF 4.9 g/kg group: model group + YSTLF 4.9 g/kg per day; YSTLF 9.8 g/k group: model group + YSTLF 9.8 g/kg per day; CTP group: model group + CTP 12.5 mg/kg per day. DKD: diabetic kidney disease mice; CON: Control group; MOD: Model group; YSTLF: Yishen Tongluo formula; CTP: Captopril group; Bax: BCL-2-associated X. Statistical analyses were measured using a one-way analysis of variance for multiple comparisons. Data were presented as mean ± standard deviation (n = 6). Compared with the control group, aP < 0.01; compared with the model group, bP < 0.01, cP < 0.05.

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Yishen Tongluo formula (益肾通络方) ameliorates kidney injury via modulating inflammation and apoptosis in streptozotocin-induced diabetic kidney disease mice

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