The anti-inflammatory and antifibrotic effects of Coreopsis tinctoria Nutt on high-glucose-fat diet and streptozotocin-induced diabetic renal damage in rats

BMC Complementary and Alternative Medicine

Xinmin Mao²  Jian Wang¹  Rui Zhang¹  Yujie Zhang²  Hui Li³  Xinxia Li³  Linlin Li¹  Lan Yao² 

[1] College of Basic Medical Sciences, Xinjiang Medical University, Xinyi Street 393, Urumuqi 830011, China;College of Traditional Chinese Medicine, Xinjiang Medical University, Xinyi Street 393, Urumuqi 830011, China;Center of Analysis and Test, Xinjiang Medical University, Xinyi Street 393, Urumuqi 830011, China

关键词: Anti-fibrotic effect;    Anti-inflammatory effect;    Coreopsis tinctoria Nutt;    Diabetic nephropathy;   

Others  :  1224050
DOI  :  10.1186/s12906-015-0826-x

 received in 2015-04-22, accepted in 2015-08-25,  发布年份 2015

【 摘 要 】

Background

Diabetic nephropathy is a serious complication of diabetes whose development process is associated with inflammation, renal hypertrophy, and fibrosis. Coreopsis tinctoria Nutt, traditionally used as a healthcare tea, has anti-inflammatory, anti-hyperlipidemia, and glycemic regulation activities. The aim of our study was to investigate the renal protective effect of ethyl acetate extract of C. tinctoria Nutt (AC) on high-glucose–fat diet and streptozotocin (STZ)-induced diabetic rats.

Methods

A diabetic rat model was induced by high-glucose–fat diet and intraperitoneal injection of 35 mg/kg STZ. After treatment with AC at a daily dose of 150, 300 or, 600 mg/kg for 4 weeks, metabolic and renal function parameters of serum and urine were examined. Degree of renal damage, renal proinflammatory cytokines, and fibrotic protein expression were analyzed by histopathology and immunohistochemistry. Renal AMP-activated protein kinase (AMPK) and transforming growth factor (TGF)-β1/Smad signaling pathway were determined by western blotting.

Results

Diabetic rats showed obvious renal dysfunction, inflammation and fibrosis. However, AC significantly reduced levels of blood glucose, total cholesterol, triglyceride, blood urea nitrogen, serum creatinine and urinary albumin, as well as expression of kidney proinflammatory cytokines of monocyte chemoattractant protein-1 and intercellular adhesion molecule-1. AC also ameliorated renal hypertrophy and fibrosis by reducing fibronectin and collagen IV and suppressing the TGF-β1/Smad signaling pathway. Meanwhile, AMPKα as a protective cytokine was markedly stimulated by AC.

Conclusion

In summary, AC controls blood glucose, inhibits inflammatory and fibrotic processes, suppresses the TGF-β1/Smad signaling pathway, and activates phosphorylation of AMPKα in the kidneys, which confirms the protective effects of AC in the early stage of diabetic kidney disease.

【 授权许可】

   
2015 Yao et al.

【 图 表 】

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【 参考文献 】

• [1]Chen X, Yang W. Epidemic trend of diabetes in China: For the Xiaoren Pan Distinguished Research Award in AASD. J Diabetes Investig. 2014; 5:478-481.
• [2]Calcutt NA, Cooper ME, Kern TS, Schmidt AM. Therapies for hyperglycaemia-induced diabetic complications: from animal models to clinical trials. Nat Rev Drug Discov. 2009; 8:417-429.
• [3]Kanasaki K, Taduri G, Koya D. Diabetic nephropathy: the role of inflammation in fibroblast activation and kidney fibrosis. Front Endocrinol (Lausanne). 2013; 4:7.
• [4]Soetikno V, Arozal W, Louisa M, Setiabudy R. New insight into the molecular drug target of diabetic nephropathy. Int J Endocrinol. 2014; 2014:968681.
• [5]Lim A. Diabetic nephropathy–complications and treatment. Int J Nephrol Renovasc Dis. 2014; 7:361-381.
• [6]Zhuo L, Zou G, Li W, Lu J, Ren W. Prevalence of diabetic nephropathy complicating non-diabetic renal disease among Chinese patients with type 2 diabetes mellitus. Eur J Med Res. 2013; 18:4. BioMed Central Full Text
• [7]Ayodele OE, Alebiosu CO, Salako BL. Diabetic nephropathy--a review of the natural history, burden, risk factors and treatment. J Natl Med Assoc. 2004; 96:1445-1454.
• [8]Kolset SO, Reinholt FP, Jenssen T. Diabetic nephropathy and extracellular matrix. J Histochem Cytochem. 2012; 60:976-986.
• [9]Mason RM, Wahab NA. Extracellular matrix metabolism in diabetic nephropathy. J Am Soc Nephrol. 2003; 14:1358-1373.
• [10]Jackle-Meyer I, Szukics B, Neubauer K, Metze V, Petzoldt R, Stolte H. Extracellular matrix proteins as early markers in diabetic nephropathy. Eur J Clin Chem Clin Biochem. 1995; 33:211-219.
• [11]Ziyadeh FN. The extracellular matrix in diabetic nephropathy. Am J Kidney Dis. 1993; 22:736-744.
• [12]Parving HH, Brenner BM, McMurray JJ, de Zeeuw D, Haffner SM, Solomon SD, Chaturvedi N, Persson F, Desai AS, Nicolaides M, Richard A, Xiang Z, Brunel P, Pfeffer MA, Investigators A. Cardiorenal end points in a trial of aliskiren for type 2 diabetes. N Engl J Med. 2012; 367:2204-2213.
• [13]Cooper ME. Diabetes: treating diabetic nephropathy-still an unresolved issue. Nat Rev Endocrinol. 2012; 8:515-516.
• [14]Wada J, Makino H. Inflammation and the pathogenesis of diabetic nephropathy. Clin Sci (Lond). 2013; 124:139-152.
• [15]Garcia-Garcia PM, Getino-Melian MA, Dominguez-Pimentel V, Navarro-Gonzalez JF. Inflammation in diabetic kidney disease. World J Diabetes. 2014; 5:431-443.
• [16]Werth S, Lehnert H, Steinhoff J. Diabetic nephropathy: Current diagnostics and treatment. Internist (Berl). 2015;56:513–9. doi:10.1007/s00108-014-3629-0.
• [17]Xu XX, Zhang W, Zhang P, Qi XM, Wu YG, Shen JJ. Superior renoprotective effects of the combination of breviscapine with enalapril and its mechanism in diabetic rats. Phytomedicine. 2013; 20:820-827.
• [18]Wang W, Chen W, Yang Y, Liu T, Yang H, Xin Z. New Phenolic Compounds from Coreopsis tinctoria Nutt. and Their Antioxidant and Angiotensin I-Converting Enzyme Inhibitory Activities. J Agric Food Chem. 2014; 63:200-207.
• [19]Li Y, Chen X, Xue J, Liu J, Chen X, Wulasihan M. Flavonoids furom Coreopsis tinctoria adjust lipid metabolism in hyperlipidemia animals by down-regulating adipose differentiation-related protein. Lipids Health Dis. 2014; 13:193-211. BioMed Central Full Text
• [20]Dias T, Bronze MR, Houghton PJ, Mota-Filipe H, Paulo A. The flavonoid-rich fraction of Coreopsis tinctoria promotes glucose tolerance regain through pancreatic function recovery in streptozotocin-induced glucose-intolerant rats. J Ethnopharmacol. 2010; 132:483-490.
• [21]Zhang Y, Shi S, Zhao M, Chai X, Tu P. Coreosides A-D, C14-polyacetylene glycosides from the capitula of Coreopsis tinctoria and its anti-inflammatory activity against COX-2. Fitoterapia. 2013; 87:93-97.
• [22]Lu HJ, Tzeng TF, Liou SS, Da Lin S, Wu MC, Liu IM. Ruscogenin ameliorates diabetic nephropathy by its anti-inflammatory and anti-fibrotic effects in streptozotocin-induced diabetic rat. BMC Complement Altern Med. 2014; 14:110-222. BioMed Central Full Text
• [23]Tesch GH. MCP-1/CCL2: a new diagnostic marker and therapeutic target for progressive renal injury in diabetic nephropathy. Am J Physiol Renal Physiol. 2008; 294:697-701.
• [24]Morii T, Fujita H, Narita T, Shimotomai T, Fujishima H, Yoshioka N, Imai H, Kakei M, Ito S. Association of monocyte chemoattractant protein-1 with renal tubular damage in diabetic nephropathy. J Diabetes Complications. 2003; 17:11-15.
• [25]Cheng J, Diaz Encarnacion MM, Warner GM, Gray CE, Nath KA, Grande JP. TGF-beta1 stimulates monocyte chemoattractant protein-1 expression in mesangial cells through a phosphodiesterase isoenzyme 4-dependent process. Am J Physiol Cell Physiol. 2005; 289:959-970.
• [26]Gu HF, Ma J, Gu KT, Brismar K. Association of intercellular adhesion molecule 1 (ICAM1) with diabetes and diabetic nephropathy. Front Endocrinol (Lausanne). 2012; 3:179.
• [27]Goldfarb S, Ziyadeh FN. TGF-beta: a crucial component of the pathogenesis of diabetic nephropathy. Trans Am Clin Climatol Assoc. 2001; 112:27-32.
• [28]Chen S, Jim B, Ziyadeh FN. Diabetic nephropathy and transforming growth factor-beta: transforming our view of glomerulosclerosis and fibrosis build-up. Semin Nephrol. 2003; 23:532-543.
• [29]Lan HY. Diverse roles of TGF-beta/Smads in renal fibrosis and inflammation. Int J Biol Sci. 2011; 7:1056-1067.
• [30]Lan HY, Chung AC. Transforming growth factor-beta and Smads. Contrib Nephrol. 2011; 170:75-82.
• [31]Lan HY. Transforming growth factor-beta/Smad signalling in diabetic nephropathy. Clin Exp Pharmacol Physiol. 2012; 39:731-738.
• [32]Kemp BE, Stapleton D, Campbell DJ, Chen ZP, Murthy S, Walter M, Gupta A, Adams JJ, Katsis F, van Denderen B, Jennings IG, Iseli T, Michell BJ, Witters LA. AMP-activated protein kinase, super metabolic regulator. Biochem Soc Trans. 2003; 31:162-168.
• [33]Davies SP, Carling D, Hardie DG. Tissue distribution of the AMP-activated protein kinase, and lack of activation by cyclic-AMP-dependent protein kinase, studied using a specific and sensitive peptide assay. Eur J Biochem. 1989; 186:123-128.
• [34]Hawley SA, Davison M, Woods A, Davies SP, Beri RK, Carling D, Hardie DG. Characterization of the AMP-activated protein kinase kinase from rat liver and identification of threonine 172 as the major site at which it phosphorylates AMP-activated protein kinase. J Biol Chem. 1996; 271:27879-27887.
• [35]Decleves AE, Mathew AV, Cunard R, Sharma K. AMPK mediates the initiation of kidney disease induced by a high-fat diet. J Am Soc Nephrol. 2011; 22:1846-1855.
• [36]Hallows KR, Mount PF, Pastor-Soler NM, Power DA. Role of the energy sensor AMP-activated protein kinase in renal physiology and disease. Am J Physiol Renal Physiol. 2010; 298:1067-1077.
• [37]Mishra R, Cool BL, Laderoute KR, Foretz M, Viollet B, Simonson MS. AMP-activated protein kinase inhibits transforming growth factor-beta-induced Smad3-dependent transcription and myofibroblast transdifferentiation. J Biol Chem. 2008; 283:10461-10469.
• [38]Jeong HW, Hsu KC, Lee JW, Ham M, Huh JY, Shin HJ, Kim WS, Kim JB. Berberine suppresses proinflammatory responses through AMPK activation in macrophages. Am J Physiol Endocrinol Metab. 2009; 296:955-964.
• [39]Lee MJ, Feliers D, Mariappan MM, Sataranatarajan K, Mahimainathan L, Musi N, Foretz M, Viollet B, Weinberg JM, Choudhury GG, Kasinath BS. A role for AMP-activated protein kinase in diabetes-induced renal hypertrophy. Am J Physiol Renal Physiol. 2007; 292:617-627.
• [40]Zhao J, Miyamoto S, You YH, Sharma K. AMP-activated protein kinase (AMPK) activation inhibits nuclear translocation of Smad4 in mesangial cells and diabetic kidneys. Am J Physiol Renal Physiol 2015, 308:F1167-77. doi:10.1152/ajprenal.00234.2014