Diabetic nephropathy (DN) is one of the most common causes of end-stage renal failure. This study was performed to determine the effect of Dantonic Pill (DP) treatment on β-catenin expression in a rat model of streptozotocin- (STZ-) induced early-stage DN, with irbesartan treatment as a positive control. Including an analysis of the general metabolic index and renal function, immunohistochemical staining and reverse transcription real-time PCR for β-catenin were performed in the renal cortex of the rat models every 4 weeks. After the treatments of DP and irbesartan, the albuminuria level, kidney weight/body weight, and thickness of the glomerular basement membrane were decreased, but the expression of β-catenin was not downregulated in the renal cortex. The effective drug target of DP to ameliorate albuminuria and renal hypertrophy should not inhibit the upregulated expression of β-catenin in rats with STZ-induced early-stage diabetic damage. 1. Introduction Diabetes mellitus presents a significant health concern because this disorder leads to long-term complications throughout the body involving the renal and other systems [1]. Diabetic nephropathy (DN) evolves into a progressive fibrosing kidney disease. Wnt pathway components have been reported to be associated with various kidney diseases including DN [2]. Regulating the -catenin protein levels to control the activation of Wnt-responsive target genes is referred to as the canonical Wnt/ -catenin pathway. Wnt proteins interact with receptor proteins and stabilize the downstream transcription regulator -catenin by inhibiting -catenin phosphorylation, which reportedly affects tubule formation and epithelial differentiation [3]. High glucose levels (HG) increased the phosphorylation of -catenin and reduced the nuclear -catenin levels. The destabilization of -catenin was correlated with the increased expression of other profibrotic factors in mesangial cells [4]. Impaired -catenin signaling is one prominent pathologic reaction responsible for the ECM metabolism induced by HG in mesangial cells [5]. “Herbal medicines’’ and ‘‘herbal remedies’’ are interchangeable terms that are used to refer to treatments containing various mixtures of herbs. People choose to take herbal medicines as alternatives to orthodox medicines due to their supposed low levels of toxicity and their ‘‘natural’’ origins. Thousands of years ofclinic practice in traditional Chinese medicine (TCM) have accumulated a considerable number of formulae that exhibit reliable in vivo efficacy and safety. The “Dantonic Pill” (DP), also known as
References
[1]
D. Daneman, “Type 1 diabetes,” The Lancet, vol. 367, no. 9513, pp. 847–858, 2006.
[2]
K. Pulkkinen, S. Murugan, and S. Vainio, “Wnt signaling in kidney development and disease,” Organogenesis, vol. 4, no. 2, pp. 55–59, 2008.
[3]
S. Kuure, A. Popsueva, M. Jakobson, K. Sainio, and H. Sariola, “Glycogen synthase kinase-3 inactivation and stabilization of β-catenin induce nephron differentiation in isolated mouse and rat kidney mesenchymes,” Journal of the American Society of Nephrology, vol. 18, no. 4, pp. 1130–1139, 2007.
[4]
C. L. Lin, J. Y. Wang, Y. T. Huang, et al., “Wnt/β-catenin signaling modulates survival of high glucose-stressed glomerular mesangial cells,” Journal of the American Society of Nephrology, vol. 17, no. 10, pp. 2812–2820, 2006.
[5]
C. L. Lin, J. Y. Wang, J. Y. Ko, et al., “Dickkopf-1 promotes hyperglycemia-induced accumulation of mesangial matrix and renal dysfunction,” Journal of the American Society of Nephrology, vol. 21, no. 1, pp. 124–135, 2010.
[6]
X. J. Zhou, L. Li, L. J. Zhou et al., “Effect of compound Danshen dropping pills on microalbuminuria in type 2 diabetic patients with nephropathy,” Chinese Journal of New Drugs, vol. 18, no. 15, pp. 1427–1429, 2009.
[7]
P. A. De Smet, “Drug therapy: herbal remedies,” The New England Journal of Medicine, vol. 347, no. 25, pp. 2046–2056, 2002.
[8]
I. M. Liu, T. F. Tzeng, S. S. Liou, and C. J. Chang, “The amelioration of streptozotocin diabetes-induced renal damage by Wu-Ling-San (Hoelen Five Herb Formula), a traditional Chinese prescription,” Journal of Ethnopharmacology, vol. 124, no. 2, pp. 211–218, 2009.
[9]
F. Zheng, Y. J. Zeng, A. R. Plati et al., “Combined AGE inhibition and ACEi decreases the progression of established diabetic nephropathy in B6 db/db mice,” Kidney International, vol. 70, no. 3, pp. 507–514, 2006.
[10]
X. P. Zhang, J. Jiang, Y. P. Yu, Q. H. Cheng, and B. Chen, “Effect of Danshen on apoptosis and NF-κB protein expression of the intestinal mucosa of rats with severe acute pancreatitis or obstructive jaundice,” Hepatobiliary and Pancreatic Diseases International, vol. 9, no. 5, pp. 537–546, 2010.
[11]
R. D. Sonawane, S. L. Vishwakarma, S. Lakshmi, M. Rajani, H. Padh, and R. K. Goyal, “Amelioration of STZ-induced type 1 diabetic nephropathy by aqueous extract of Enicostemma littorale Blume and swertiamarin in rats,” Molecular and Cellular Biochemistry, vol. 340, no. 1-2, pp. 1–6, 2010.
[12]
A. B. Fogo, “Diabetic nephropathy: it's in the numbers,” Kidney International, vol. 61, no. 6, pp. 2274–2275, 1998.
[13]
M. Shimamura, H. Nakagami, T. Shimosato et al., “Irbesartan improves endothelial dysfunction, abnormal lipid profile, proteinuria and liver dysfunction in Zucker diabetic fatty rats independent of glucose and insulin levels,” Experimental and Therapeutic Medicine, vol. 2, no. 5, pp. 957–961, 2011.
[14]
Chinese Pharmacopoeia Commission, Pharmacopoeia of the People's Republic of China 2005 (Volumes I), vol. 528, 2005.
[15]
J. L. Zhang, M. Cui, Y. He, H. L. Yu, and D. A. Guo, “Chemical fingerprint and metabolic fingerprint analysis of Danshen injection by HPLC-UV and HPLC-MS methods,” Journal of Pharmaceutical and Biomedical Analysis, vol. 36, no. 5, pp. 1029–1035, 2005.
[16]
H. Zhang, Y. Xu, J. Wang, et al., “Effect of Danshensu on fibronectin and collagen-1 secretion induced by high glucose in human peritoneal mesotheial cells,” Zhong Nan Da Xue Xue BaoYi Xue Ban, vol. 36, no. 1, pp. 44–50, 2011.
[17]
W. Sun, L. Y. Feng, Z. J. Zhao, et al., “Study on antioxidant effects and inhibition of podocyte apoptosis of PNS on DN rat,” China Journal of Traditional Chinese Medicine and Pharmacy, vol. 26, no. 5, pp. 1061–1067, 2011.
[18]
Q. N. Tu and Y. Shi, “Protective effect of panax notoginoside on rats with type 1 diabetic nephropathy,” Journal of Internal Intensive Medicine, vol. 13, no. 5, pp. 241–242, 2007.
[19]
F. U. Zhenchun, X. U. Gang, G. E. Ting, et al., “Effects of PNS on CTGF in diabetic rats,” Chinese Archives of Traditional Chinese Medicine, vol. 26, no. 5, pp. 1042–1045, 2008.
[20]
G. Xu, M. L. Liu, Z. C. Fu, et al., “Effect of treatment with panax notoginseng saponins and aminoguanidine on nonenzymatic glycosylation in kidney of diabetic rats,” Chinese Journal of Clinicians, vol. 4, no. 4, pp. 414–420, 2010.
[21]
D. Wu and W. Pan, “GSK3: a multifaceted kinase in Wnt signaling,” Trends in Biochemical Sciences, vol. 35, no. 3, pp. 161–168, 2010.
[22]
Z. Al-Aly, J. S. Shao, C. F. Lai, et al., “Aortic Msx2-Wnt calcification cascade is regulated by TNF-α-dependent signals in diabetic Ldlr-/- mice,” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 27, no. 12, pp. 2589–2596, 2007.
[23]
H. Quasnichka, S. C. Slater, C. A. Beeching, M. Boehm, G. B. Sala-Newby, and S. J. George, “Regulation of smooth muscle cell proliferation by β-catenin/T-cell factor signaling involves modulation of cyclin D1 and p21 expression,” Circulation Research, vol. 99, no. 12, pp. 1329–1337, 2006.
[24]
C. F. Lai, V. Seshadri, K. Huang et al., “An osteopontin-NADPH oxidase signaling cascade promotes pro-matrix metalloproteinase 9 activation in aortic mesenchymal cells,” Circulation Research, vol. 98, no. 12, pp. 1479–1489, 2006.
[25]
T. Zhou, Y. Hu, Y. Chen, et al., “The pathogenic role of the canonical Wnt pathway in age-related macular degeneration,” Investigative Ophthalmology & Visual Science, vol. 51, no. 9, pp. 4371–4379, 2010.
[26]
W. He, R. Tan, C. Dai et al., “Plasminogen activator inhibitor-1 is a transcriptional target of the canonical pathway of Wnt/β-catenin signaling,” Journal of Biological Chemistry, vol. 285, no. 32, pp. 24665–24675, 2010.
[27]
W. Si, Q. Kang, H. H. Luu, et al., “CCN1/Cyr61 is regulated by the canonical Wnt signal and plays an important role in Wnt3A-induced osteoblast differentiation of mesenchymal stem cells,” Molecular and Cellular Biology, vol. 26, no. 8, pp. 2955–2964, 2006.
[28]
F. Chiarelli, S. Gaspari, and M. L. Marcovecchio, “Role of growth factors in diabetic kidney disease,” Hormone and Metabolic Research, vol. 41, no. 8, pp. 585–593, 2009.
[29]
T. Zhou, X. He, R. Cheng, et al., “Implication of dysregulation of the canonical wingless-type MMTV integration site (WNT) pathway in diabetic nephropathy,” Diabetologia, vol. 55, no. 1, pp. 255–266, 2012.
[30]
T. Ninomiya, V. Perkovic, B. E. de Galan, et al., “Albuminuria and kidney function independently predict cardiovascular and renal outcomes in diabetes,” Journal of the American Society of Nephrology, vol. 20, no. 8, pp. 1813–1821, 2009.