Tags

Type your tag names separated by a space and hit enter

Huangkui capsule in combination with metformin ameliorates diabetic nephropathy via the Klotho/TGF-β1/p38MAPK signaling pathway.
J Ethnopharmacol. 2020 Nov 03; 281:113548.JE

Abstract

ETHNOPHARMACOLOGICAL RELEVANCE

Huangkui capsule (HKC), extracted from Abelmoschus manihot (L.) medic (AM), as a patent proprietary Chinese medicine on the market for approximately 20 years, has been clinically used to treat chronic glomerulonephritis. Renal fibrosis has been implicated in the onset and development of diabetic nephropathy (DN). However, the potential application of HKC for preventing DN has not been evaluated.

AIM OF THE STUDY

This study was designed to investigate the efficacy and underlying mechanisms of HKC combined with metformin (MET), the first-line medication for treating type 2 diabetes, in the treatment of renal interstitial fibrosis.

MATERIALS AND METHODS

A rat model of diabetes-associated renal fibrosis was established by intraperitoneal injection of streptozotocin (STZ, 65 mg/kg) combined with a high-fat and high-glucose diet. The rats were randomly divided into five groups: normal control, DN, HKC (1.0 g/kg/day), MET (100 mg/kg/d), and HKC plus MET (1.0 g/kg/day + 100 mg/kg/d). Following drug administration for 8 weeks, we collected blood, urine, and kidney tissue for analysis. Biochemical markers and metabolic parameters were detected using commercial kits. Histopathological staining was performed to monitor morphological changes in the rat kidney. High-glucose-induced human kidney HK-2 cells were used to evaluate the renal protective effects of HKC combined with MET (100 μg/mL+10 mmol/L). MTT assay and acridine orange/ethidium bromide were used to examine cell proliferation inhibition rates and apoptosis. Immunofluorescence assay and Western blot analysis were performed to detect renal fibrosis-related proteins including Klotho, TGF-β1, and phosphorylated (p)-p38.

RESULTS

Combination therapy (HKC plus MET) significantly improved the weight, reduced blood glucose (BG), blood urea nitrogen (BUN), total cholesterol (T-CHO), triglycerides (TG), low-density lipoprotein (LDL) and increased the level of high-density lipoprotein (HDL) of DN rats. Combination therapy also significantly reduced urine serum creatinine (SCR) and urine protein (UP) levels as well as reduced the degrees of renal tubule damage and glomerulopathy in DN rats. Combination therapy ameliorated renal fibrosis, as evidenced by reduced levels of alpha-smooth muscle actin and fibronectin and increased expression of E-cadherin in the kidneys. Moreover, HKC plus MET alleviated the degree of DN in part via the Klotho/TGF-β1/p38MAPK signaling pathway. In vitro experiments showed that combination therapy significantly inhibited cell proliferation and apoptosis and regulated fibrosis-related proteins in high-glucose (HG)-induced HK-2 cells. Further studies revealed that combination therapy suppressed cell proliferation and fibrosis by inhibiting the Klotho-dependent TGF-β1/p38MAPK pathway.

CONCLUSIONS

HKC plus MET in combination suppressed abnormal renal cell proliferation and fibrosis by inhibiting the Klotho-dependent TGF-β1/p38MAPK pathway. Collectively, HKC combined with MET effectively improved DN by inhibiting renal fibrosis-associated proteins and blocking the Klotho/TGF-β1/p38MAPK signaling pathway. These findings improve the understanding of the pathogenesis of diabetes-associated complications and support that HKC plus MET combination therapy is a promising strategy for preventing DN.

Authors+Show Affiliations

School of Medicine, Yangzhou University, Yangzhou, 225001, Jiangsu, PR China. Electronic address: guliyuan505@163.com.School of Medicine, Yangzhou University, Yangzhou, 225001, Jiangsu, PR China. Electronic address: ysun@yzu.edu.cn.The Huangkui Research Institute of Suzhong Pharmaceutical Co, Ltd, Taizhou, 225500, Jiangsu, PR China. Electronic address: mtang@vip.sina.com.School of Medicine, Yangzhou University, Yangzhou, 225001, Jiangsu, PR China; Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, 225001, PR China; Jiangsu Key Laboratory of Integrated Traditional Chinese and Western Medicine for Prevention and Treatment of Senile Diseases, Yangzhou, 225001, PR China; Jiangsu Key Laboratory of Experimental & Translational Non-coding RNA Research, Yangzhou, 225001, PR China. Electronic address: xuzhengxin405@126.com.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

33152427

Citation

Gu, Li-Yuan, et al. "Huangkui Capsule in Combination With Metformin Ameliorates Diabetic Nephropathy Via the Klotho/TGF-β1/p38MAPK Signaling Pathway." Journal of Ethnopharmacology, vol. 281, 2020, p. 113548.
Gu LY, Yun-Sun , Tang HT, et al. Huangkui capsule in combination with metformin ameliorates diabetic nephropathy via the Klotho/TGF-β1/p38MAPK signaling pathway. J Ethnopharmacol. 2020;281:113548.
Gu, L. Y., Yun-Sun, ., Tang, H. T., & Xu, Z. X. (2020). Huangkui capsule in combination with metformin ameliorates diabetic nephropathy via the Klotho/TGF-β1/p38MAPK signaling pathway. Journal of Ethnopharmacology, 281, 113548. https://doi.org/10.1016/j.jep.2020.113548
Gu LY, et al. Huangkui Capsule in Combination With Metformin Ameliorates Diabetic Nephropathy Via the Klotho/TGF-β1/p38MAPK Signaling Pathway. J Ethnopharmacol. 2020 Nov 3;281:113548. PubMed PMID: 33152427.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Huangkui capsule in combination with metformin ameliorates diabetic nephropathy via the Klotho/TGF-β1/p38MAPK signaling pathway. AU - Gu,Li-Yuan, AU - Yun-Sun,, AU - Tang,Hai-Tao, AU - Xu,Zheng-Xin, Y1 - 2020/11/03/ PY - 2020/09/22/received PY - 2020/10/21/revised PY - 2020/10/30/accepted PY - 2020/11/6/pubmed PY - 2020/11/6/medline PY - 2020/11/5/entrez KW - Diabetic nephropathy KW - Huangkui capsule KW - Klotho KW - Metformin KW - Renal fibrosis SP - 113548 EP - 113548 JF - Journal of ethnopharmacology JO - J Ethnopharmacol VL - 281 N2 - ETHNOPHARMACOLOGICAL RELEVANCE: Huangkui capsule (HKC), extracted from Abelmoschus manihot (L.) medic (AM), as a patent proprietary Chinese medicine on the market for approximately 20 years, has been clinically used to treat chronic glomerulonephritis. Renal fibrosis has been implicated in the onset and development of diabetic nephropathy (DN). However, the potential application of HKC for preventing DN has not been evaluated. AIM OF THE STUDY: This study was designed to investigate the efficacy and underlying mechanisms of HKC combined with metformin (MET), the first-line medication for treating type 2 diabetes, in the treatment of renal interstitial fibrosis. MATERIALS AND METHODS: A rat model of diabetes-associated renal fibrosis was established by intraperitoneal injection of streptozotocin (STZ, 65 mg/kg) combined with a high-fat and high-glucose diet. The rats were randomly divided into five groups: normal control, DN, HKC (1.0 g/kg/day), MET (100 mg/kg/d), and HKC plus MET (1.0 g/kg/day + 100 mg/kg/d). Following drug administration for 8 weeks, we collected blood, urine, and kidney tissue for analysis. Biochemical markers and metabolic parameters were detected using commercial kits. Histopathological staining was performed to monitor morphological changes in the rat kidney. High-glucose-induced human kidney HK-2 cells were used to evaluate the renal protective effects of HKC combined with MET (100 μg/mL+10 mmol/L). MTT assay and acridine orange/ethidium bromide were used to examine cell proliferation inhibition rates and apoptosis. Immunofluorescence assay and Western blot analysis were performed to detect renal fibrosis-related proteins including Klotho, TGF-β1, and phosphorylated (p)-p38. RESULTS: Combination therapy (HKC plus MET) significantly improved the weight, reduced blood glucose (BG), blood urea nitrogen (BUN), total cholesterol (T-CHO), triglycerides (TG), low-density lipoprotein (LDL) and increased the level of high-density lipoprotein (HDL) of DN rats. Combination therapy also significantly reduced urine serum creatinine (SCR) and urine protein (UP) levels as well as reduced the degrees of renal tubule damage and glomerulopathy in DN rats. Combination therapy ameliorated renal fibrosis, as evidenced by reduced levels of alpha-smooth muscle actin and fibronectin and increased expression of E-cadherin in the kidneys. Moreover, HKC plus MET alleviated the degree of DN in part via the Klotho/TGF-β1/p38MAPK signaling pathway. In vitro experiments showed that combination therapy significantly inhibited cell proliferation and apoptosis and regulated fibrosis-related proteins in high-glucose (HG)-induced HK-2 cells. Further studies revealed that combination therapy suppressed cell proliferation and fibrosis by inhibiting the Klotho-dependent TGF-β1/p38MAPK pathway. CONCLUSIONS: HKC plus MET in combination suppressed abnormal renal cell proliferation and fibrosis by inhibiting the Klotho-dependent TGF-β1/p38MAPK pathway. Collectively, HKC combined with MET effectively improved DN by inhibiting renal fibrosis-associated proteins and blocking the Klotho/TGF-β1/p38MAPK signaling pathway. These findings improve the understanding of the pathogenesis of diabetes-associated complications and support that HKC plus MET combination therapy is a promising strategy for preventing DN. SN - 1872-7573 UR - https://www.unboundmedicine.com/medline/citation/33152427/Huangkui_capsule_in_combination_with_metformin_ameliorates_diabetic_nephropathy_via_the_Klotho/TGF_β1/p38MAPK_signaling_pathway_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0378-8741(20)33436-X DB - PRIME DP - Unbound Medicine ER -
Try the Free App:
Prime PubMed app for iOS iPhone iPad
Prime PubMed app for Android
Prime PubMed is provided
free to individuals by:
Unbound Medicine.