Danzhi Jiangtang capsule (丹蛭降糖胶囊) reduces renal injury in rats with diabetes induced by high fat diet and streptozotocin via downregulating toll-like receptor 4-nuclear factor-κB pathway and apoptosis

doi:10.19852/j.cnki.jtcm.20230124.001

Abstract

Abstract:

OBJECTIVE: To investigate the effect and mechanisms of Danzhi Jiangtang capsule (丹蛭降糖胶囊, DJC) on renal injury in streptozotocin (STZ)-induced diabetes of rats.

METHODS: Sprague-Dawley rats were fed with high fat diet for 6 weeks followed by streptozotocin (STZ, 35 mg/kg) injection. These rats were then treated with DJC (270, 540 and 1080 mg/kg) daily for 8 weeks.

RESULTS: A combination of high fat diet and STZ significantly increased blood glucose creatinine, urea nitrogen, and urine albumin in rats. Meanwhile, the glomerular and tubular lesions were observed in rats fed with high fat diet and injected with STZ. These biochemical and pathological changes were significantly attenuated by DJC treatments in a dose-dependent manner. Mechanistically, DJC treatments significantly decreased toll-like receptor 4 (TLR4), mitogen-activated protein kinase (MAPK), and nuclear factor-κB (NF-κB) signals in the kidney of rats fed with high fat diet and injected with STZ. Terminal deoxynucleotidyl transferase dUTP nick end labeling staining and caspase-8 levels showed that renal apoptosis was increased in rats fed with high fat diet and injected with STZ, and this was attenuated by DJC treatments.

CONCLUSIONS: DJC treatments protect against diabetic kidney disease, and the mechanism may be closely related to downregulation of TLR4/MAPK/NF-κB pathways and apoptosis. This study provides further evidence of using DJC as a potential therapeutic option for diabetic kidney disease.

Key words: diabetic nephropathies, inflammation, apoptosis, toll-like receptor 4, mitogen-activated protein kinase kinases, NF-kappa B, Danzhi Jiangtang capsule

XIE Jing, BI Zheng, WANG Sihai, SHEN Guoming, FANG Zhaohui. Danzhi Jiangtang capsule (丹蛭降糖胶囊) reduces renal injury in rats with diabetes induced by high fat diet and streptozotocin via downregulating toll-like receptor 4-nuclear factor-κB pathway and apoptosis[J]. Journal of Traditional Chinese Medicine, 2023, 43(2): 312-321.

Figures/Tables 11

Table 1 Effect of DJC on body weight in rats fed with HFD and injected with STZ

Feeding week	Control (n = 8)	HFD/STZ (n = 8)	HFD/STZ+Val (n = 8)	HFD/STZ+DJC (270) (n = 8)	HFD/STZ+DJC (540) (n = 8)	HFD/STZ+DJC (1080) (n = 8)
0	171±17	173±18	168±18	163±18	181±18	174±18
1	201±18	188±19	195±18	178±18	190±19	188±19
2	232±19	198±19	204±19	190±19	198±19	203±20
3	257±20	199±19	215±19	196±19	205±20	209±20
4	275±21	193±19^ab	219±19^ab	207±20^ab	221±20^ab	220±20^ab
5	295±22	183±19^bc	226±18^bc	217±20^bc	233±21^bc	228±21^bc
6	310±23	179±18^bc	233±19^bc	226±21^bc	242±22^bc	242±21^bc
7	323±24	167±18^bc	238±18^bc	229±21^bc	254±22^bc	250±22^bc
8	330±24	157±17^bd	240±15^bd	234±21^bd	264±23^bc	257±22^bd

Table 2 Effect of DJC on food intake in rats fed with HFD and injected with STZ

Feeding week	Control (n = 8)	HFD/STZ (n = 8)	HFD/STZ+Val (n = 8)	HFD/STZ+DJC (270) (n = 8)	HFD/STZ+DJC (540) (n = 8)	HFD/STZ+DJC (1080) (n = 8)
0	27.2±1.4	23.7±1.2	25.2±1.2	24.3±1.2^a	23.6±1.2	23.6±1.2
1	27.3±1.3	24.9±1.2	25.5±1.3	26.1±1.3^a	25.7±1.3	24.3±1.2
2	28.9±1.4	25.6±1.3	26.1±1.3	26.1±1.3^a	24.7±1.2	26.8±1.3
3	29.3±1.5	27.8±1.4	26.6±1.3	25.7±1.3^a	27.1±1.4	25.7±1.3
4	28.7±1.4	29.3±1.5	25.8±1.3	27.4±1.4^a	26.4±1.3	27.1±1.3
5	29.1±1.4	30.2±1.5	27.1±1.4	29.5±1.5^a	27.9±1.4	27.4±1.4
6	29.5±1.5	32.9±1.6	28.4±1.4	30.7±1.5^a	29.1±1.4	28.4±1.4
7	30.6±1.5	33.9±1.7	30.2±1.5	31.5±1.6^a	30.8±1.5	32.4±1.6
8	31.4±1.6^c	37.3±1.8^c	30.3±1.5^c	34.7±1.7^ac	32.1±1.6^c	32.3±1.6^c

Table 3 Effect of DJC treatments on blood glucose in rats fed with HFD and injected with STZ (mmol/L)

Group		n	Before treatment	After treatment
Control	-	8	5.5±0.6	5.9±0.7
HFD/STZ	Vehicle	8	21.5±2.0^a	24.9±2.2^a
	Valsartan group	8	21.3±1.9^a	20.1±2.2^a
	DJC (270 mg/kg)	8	21.6±2.5^a	19.0±1.0^a,b
	DJC (540 mg/kg)	8	21.7±2.4^a	16.7±1.2^a,b
	DJC (1080 mg/kg)	8	22.2±2.1^a	16.3±2.1^a

Table 4 Effect of DJC treatments on blood creatinine and urea nitrogen in diabetic rats (μmol/L)

Group		n	Creatinine	Urea nitrogen
Control	-	8	27.6±5.7	4.1±1.2
HFD/STZ	Vehicle	8	66.9±16.9^a	8.0±2.9^a
	Valsartan group	8	58.8±11.8^bc	5.6±1.9^ac
	DJC (270 mg/kg)	8	53.6±14.2^abd	7.3±1.9^acd
	DJC (540 mg/kg)	8	48.0±13.2^abd	6.1±1.7^acd
	DJC (1080 mg/kg)	8	42.3±12.5^ac	5.4±1.8^ac

Table 5 Effect of DJC treatments on creatinine and urea nitrogen in the urine of diabetic rats (mg/dL)

Group		n	Creatinine	Urea
Control	-	8	68.44±6.80	2.43±0.54
HFD/STZ	Vehicle	8	20.29±3.28^a	0.49±0.11^a
	Valsartan group	8	62.75±9.66^b	2.19±0.40^b
	DJC (270 mg/kg)	8	26.00±5.70^c	0.58±0.10^c
	DJC (540 mg/kg)	8	34.63±5.95^d	1.03±0.20^d
	DJC (1080 mg/kg)	8	54.75±10.10^b	2.04±0.45^b

Table 6 Effect of DJC treatments on albumin in the urine of diabetic rats (mg/24 h)

Group		n	Before treatment	After treatment
Control	-	8	9.0±2.5	9.5±2.1
HFD/STZ	Vehicle	8	45.6±3.5^a	48.3±3.7^a
	Valsartan group	8	47.9±3.6^a	39.2±2.5^ab
	DJC (270 mg/kg)	8	46.9±3.6^a	36.8±2.7^abc
	DJC (540 mg/kg)	8	45.3±3.5^a	31.7±2.8^ab
	DJC (1080 mg/kg)	8	46.9±3.5^a	30.6±2.5^ab

Figure 1 Effect of DJC on kidney morphology in rats fed with HFD and injected with STZ A: control group; B: HFD/STZ vehicle group; C: HFD/STZ + Valsartan group; D: HFD/STZ + DJC group; E: HFD/STZ+ DJC group; F: HFD/STZ + DJC group. HE staining was performed in the kidney of rats fed with HFD and injected with STZ in the presence or absence of DJC treatments. Arrows show pathological changes. n = 8. × 400 magnification. Control group: Valsartan 4.8 mg/kg; HFD/STZ vehicle group: high fat diet for 6 weeks followed by streptozotocin (STZ, 35 mg/kg) injection; HFD/STZ + Valsartan group: high fat diet for 6 weeks followed by streptozotocin (STZ, 35 mg/kg) injection, Valsartan 4.8 mg/kg; HFD/STZ + DJC group: fed with high fat diet for 6 weeks followed by streptozotocin (STZ, 35 mg/kg) injection. DJC (270 mg/kg) daily for 8 weeks; HFD/STZ + DJC group: fed with high fat diet for 6 weeks followed by streptozotocin (STZ, 35 mg/kg) injection. DJC (540 mg/kg) daily for 8 weeks; HFD/STZ + DJC group: fed with high fat diet for 6 weeks followed by streptozotocin (STZ, 35 mg/kg) injection. DJC (1080 mg/kg) daily for 8 weeks. DJC: Danzhi Jiangtang capsule; HFD: high fat and high sugar diet; STZ: streptozotocin.

Figure 2 Effect of DJC on kidney basement membranes in rats fed with HFD and injected with STZ PASM staining was performed in the kidney of rats fed with HFD and injected with STZ in the presence or absence of DJC treatments. × 400 magnification. Arrows show pathological changes. A: control group; B: HFD/STZ vehicle group; C: HFD/STZ + Valsartan group; D: HFD/STZ + DJC group (fed with high fat diet for 6 weeks followed by streptozotocin (STZ, 35 mg/kg) injection; DJC (270 mg/kg) daily for 8 weeks); E: HFD/STZ + DJC group ((fed with high fat diet for 6 weeks followed by streptozotocin (STZ, 35 mg/kg) injection; DJC (540 mg/kg) daily for 8 weeks)); F: HFD/STZ + DJC group (fed with high fat diet for 6 weeks followed by streptozotocin (STZ, 35 mg/kg) injection; DJC (1080 mg/kg) daily for 8 weeks); G: PASM value of each group. Control group: Valsartan 4.8 mg/kg; HFD/STZ vehicle group: high fat diet for 6 weeks followed by streptozotocin (STZ, 35 mg/kg) injection; HFD/STZ + Valsartan group: high fat diet for 6 weeks followed by streptozotocin (STZ, 35 mg/kg) injection, Valsartan 4.8 mg/kg; HFD/STZ + DJC group: fed with high fat diet for 6 weeks followed by streptozotocin (STZ, 35 mg/kg) injection. DJC (270 mg/kg) daily for 8 weeks; HFD/STZ + DJC group: fed with high fat diet for 6 weeks followed by streptozotocin (STZ, 35 mg/kg) injection. DJC (540 mg/kg) daily for 8 weeks; HFD/STZ+ DJC group: fed with high fat diet for 6 weeks followed by streptozotocin (STZ, 35 mg/kg) injection. DJC (1080 mg/kg) daily for 8 weeks. Ctr: control group; DJC: Danzhi Jiangtang capsule; HFD: high fat diet; PASM: periodic acid-silver methenamine; STZ: streptozotocin; HFD/STZ: both high fat diet and streptozotocin; Val: valsartan. Data were shown as mean ± standard error of mean (n = 8). aP < 0.05 vs control group; bP < 0.05 vs HFD/STZ vehicle.

Figure 3 Effect of DJC on TLR4 and NF-κB signals in the kidney of diabetic rats Western blot was performed to detect protein levels of TLR4, MyD88, MAP3K7, IκBα, and p65/NF-κB in the kidney of diabetic rats. Representative bands are present in left panel, while densitometry of bands normalized into β-actin are shown in right panel. A: Western blot analysis of TLR4, MyD88, MAP3K7, IκBα, p65/NF-κB proteins and β-actin); B-F: densitometry of proteins of TLR4, MyD88, MAP3K7, IκBα, and p65/NF-κB. Ctr: control group (Valsartan 4.8 mg/kg); Veh: HFD/STZ vehicle group (high fat diet for 6 weeks followed by streptozotocin (STZ, 35 mg/kg) injection); HFD/STZ + DJC (270): HFD/STZ + DJC group (fed with high fat diet for 6 weeks followed by streptozotocin (STZ, 35 mg/kg) injection. DJC (270 mg/kg) daily for 8 weeks); HFD/STZ + DJC (540): HFD/STZ+ DJC group (fed with high fat diet for 6 weeks followed by streptozotocin (STZ, 35 mg/kg) injection. DJC (540 mg/kg) daily for 8 weeks); HFD/STZ + DJC (1080): HFD/STZ + DJC group (fed with high fat diet for 6 weeks followed by streptozotocin (STZ, 35 mg/kg) injection. DJC (1080 mg/kg) daily for 8 weeks); HFD/STZ + Val: HFD/STZ+ Valsartan group (high fat diet for 6 weeks followed by streptozotocin (STZ, 35 mg/kg) injection, Valsartan 4.8 mg/kg. Ctr: control group; DJC: Danzhi Jiangtang capsule; HFD: high fat diet; IκBα：the major NF-κB inhibitor protein in most cells; MAP3K7: Mitogen-activated protein kinase kinase kinase 7; MyD88: Myeloid differentiation primary response 88; p65/NF-κB: a protein in the family of nuclear factor kappa-light-chain-enhancer of activated B cells; STZ: streptozotocin; TLR4: a transmembrane protein, member of the toll-like receptor family; Val: valsartan; β-actin: a cytoskeletal actin isoform in the family of the actin protein families. Data were shown as mean ± standard error of mean (n = 8). aP < 0.001 vs control (Ctr) group; bP < 0.01, cP < 0.001 vs HFD/STZ vehicle.

Table 7 Gene expression of TLR4 and NF-κB signals in the kidney of diabetic rats treated with or without DJC

Group		n	TLR4	MyD88	MAP3K	IκBα		p65/NF-κB
Control	-	8	1.01±0.12	1.00±0.18	1.01±0.13		1.01±0.16	1.00±0.10
Hfd/Stz	Vehicle	8	3.15±0.31^a	2.67±0.21^a	2.11±0.2^a	0.46±0.05^a		1.94±0.18^a
	Valsartan	8	2.91±0.30	2.36±0.28^c	1.78±0.18	0.47±0.10		1.77±0.17^b
	DJC (270 mg/kg)	8	2.081±0.20^d	2.16±0.21^d	1.72±0.16^c	0.69±0.08^d		1.64±0.16^c
	DJC (540 mg/kg)	8	1.70±0.18^d	1.16±0.13^d	1.35±0.12^d	0.8±0.1^d		1.29±0.11^d
	DJC (1080 mg/kg)	8	1.70±0.17^d	1.34±0.13^d	1.37±0.15^d	0.80±0.09^d		1.14±0.12^d

Figure 4 Effect of DJC on apoptosis in the kidney of diabetic rats A-G: TUNEL staining was performed in the kidney of diabetic rats treated with or without DJC. TUNEL positive cells are shown in brown (arrows). A: Ctr; B: HFD/STZ; C: HFD/STZ + Val; D: HFD/STZ + DJC (270); E: HFD/STZ + DJC (540); F: HFD/STZ + DJC (1080); H: caspase-8 levels and β-actin levels in the kidney of diabetic rats treated with or without DJC were measured by Western blot and qRT-PCR; I-J: densitometry and mRNA of related proteins. Control group: Valsartan 4.8 mg/kg; HFD/STZ vehicle group: high fat diet for 6 weeks followed by streptozotocin (STZ, 35 mg/kg) injection; HFD/STZ + Valsartan group: high fat diet for 6 weeks followed by streptozotocin (STZ, 35 mg/kg) injection, Valsartan 4.8 mg/kg; HFD/STZ + DJC group: fed with high fat diet for 6 weeks followed by streptozotocin (STZ, 35 mg/kg) injection. DJC (270 mg/kg) daily for 8 weeks; HFD/STZ + DJC group: fed with high fat diet for 6 weeks followed by streptozotocin (STZ, 35 mg/kg) injection. DJC (540 mg/kg) daily for 8 weeks; HFD/STZ+ DJC group: fed with high fat diet for 6 weeks followed by streptozotocin (STZ, 35 mg/kg) injection. DJC (1080 mg/kg) daily for 8 weeks. TUNEL: terminal deoxynucleotidyl transferase dUTP nick end labeling; Ctr: control group; DJC: Danzhi Jiangtang capsule; HFD: high fat diet; STZ: streptozotocin; qRT-PCR: qualitative reverse transcription polymerase chain reaction; Val: valsartan. Data were shown as mean ± standard error of mean (n = 8). aP < 0.001 vs control (Ctr) group; bP < 0.05, cP < 0.01, dP < 0.001 vs HFD/STZ vehicle.

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