期刊论文详细信息
BMC Complementary and Alternative Medicine
Qiwei granules alleviates podocyte lesion in kidney of diabetic KK-Ay mice
Tonghua Liu3  Ming Gao2  Tunhai Xu3  Xinli Wu3  Yan Zhang3  Lili Wu3  Xiangyu Guo3  Lingling Qin3  Linyi Li3  Hisae Yoshitomi2  Wen Sun3  Jingxin Zhou1 
[1] Dongzhimen Hospital Eastern Affilated to Beijing University of Chinese Medicine, 116 Cuiping West Road, Tongzhou District, Beijing, 100029, People’s Republic of China;School of Pharmaceutical Sciences, Mukogawa Women’s University, 11-68 Koshien Kyuban-cho, Nishinomiya 663-8179, Hyogo, Japan;Beijing University of Chinese Medicine, 11 North 3rd-ring East Road, Chaoyang District, Beijing, 100029, People’s Republic of China
关键词: Akt signaling pathway;    Slit diaphragm;    Podocyte;    KK-Ay mice;    Diabetic nephropathy;    Qiwei granules;   
Others  :  1219792
DOI  :  10.1186/s12906-015-0603-x
 received in 2014-07-22, accepted in 2015-03-09,  发布年份 2015
PDF
【 摘 要 】

Background

Chinese medicine comprised of all natural herbs is widespread used in the treatment of diabetic nephropathy (DN). Podocyte contributes to the integrity of glomerular filtration barrier whose injury plays an important role in the initiation and progression of DN. Our study aimed to investigate the effect of Qiwei granules on podocyte lesion in diabetic KK-Ay mice kidney and its underlying mechanism.

Methods

Twelve-week-old male KK-Ay mice were randomly divided in vehicle group and Qiwei granules group, while C57BL/6J mice were used as normal control. The mice were gavage with 1.37 g/kg/day Qiwei granules or water for 10 weeks. We measured water, food intake and body weight (BW) and fasting blood glucose (FBG) every 2 weeks, and urine protein every 4 weeks. At the end of the experiment, all surviving mice were sacrificed. The kidney weight and serum renal parameters were measured, and the renal morphology was observed. To search the underlying mechanism, we examined the podocyte positive marker, slit diaphragm protein expression and some involved cell signal pathway.

Results

Qiwei granules treatment significantly improved the metabolic parameters, alleviated the urinary protein, and protected renal function in KK-Ay mice. In addition, the glomerular injuries and podocyte lesions were mitigated with Qiwei granules treatment. Furthermore, Qiwei granules increased expression of nephrin, CD2AP, and integrin alpha3beta1 in the podocytes of KK-Ay mice. Qiwei granules improved the phosphoration of Akt and inhibited cleaved caspase-3 protein expression.

Conclusion

These finding suggest that Qiwei granules protects the podocyte from the development of DN via improving slit diaphragm (SD) molecules expression and likely activating Akt signaling pathway in KK-Ay mice.

【 授权许可】

   
2015 Zhou et al.; licensee BioMed Central.

【 预 览 】
附件列表
Files Size Format View
20150719011124877.pdf 2928KB PDF download
Figure 7. 24KB Image download
Figure 6. 24KB Image download
Figure 5. 22KB Image download
Figure 4. 79KB Image download
Figure 3. 35KB Image download
Figure 2. 113KB Image download
Figure 1. 15KB Image download
【 图 表 】

Figure 1.

Figure 2.

Figure 3.

Figure 4.

Figure 5.

Figure 6.

Figure 7.

【 参考文献 】
  • [1]Whaley-Connell A, Sowers JR, McCullough PA, Roberts T, McFarlane SI, Chen SC et al.. Diabetes mellitus and CKD awareness: the Kidney Early Evaluation Program (KEEP) and National Health and Nutrition Examination Survey (NHANES). Am J Kidney Dis. 2009; 53:S11-21.
  • [2]Tervaert TW, Mooyaart AL, Amann K, Cohen AH, Cook HT, Drachenberg CB et al.. Pathologic classification of diabetic nephropathy. J Am Soc Nephrol. 2010; 21:556-63.
  • [3]White KE, Bilous RW. Structural alterations to the podocyte are related to proteinuria in type 2 diabetic patients. Nephrol Dial Transplant. 2004; 19:1437-40.
  • [4]Susztak K, Raff AC, Schiffer M, Bottinger EP. Glucose-induced reactive oxygen species cause apoptosis of podocytes and podocyte depletion at the onset of diabetic nephropathy. Diabetes. 2006; 55:225-33.
  • [5]Satchell SC, Braet F. Glomerular endothelial cell fenestrations: an integral component of the glomerular filtration barrier. Am J Physiol Renal Physiol. 2009; 296:F947-56.
  • [6]Roselli S, Heidet L, Sich M, Henger A, Kretzler M, Gubler MC et al.. Early glomerular filtration defect and severe renal disease in podocin-deficient mice. Mol Cell Biol. 2004; 24:550-60.
  • [7]Schwarz K, Simons M, Reiser J, Saleem MA, Faul C, Kriz W et al.. Podocin, a raft-associated component of the glomerular slit diaphragm, interacts with CD2AP and nephrin. J Clin Invest. 2001; 108:1621-9.
  • [8]Jim B, Ghanta M, Qipo A, Fan Y, Chuang PY, Cohen HW et al.. Dysregulated nephrin in diabetic nephropathy of type 2 diabetes: a cross sectional study. PLoS One. 2012; 7:e36041.
  • [9]Toyoda M, Suzuki D, Umezono T, Uehara G, Maruyama M, Honma M et al.. Expression of human nephrin mRNA in diabetic nephropathy. Nephrol Dial Transplant. 2004; 19:380-5.
  • [10]Benzing T. Signaling at the slit diaphragm. J Am Soc Nephrol. 2004; 15:1382-91.
  • [11]Kagami S, Kondo S. Beta1-integrins and glomerular injury. J Med Invest. 2004; 51:1-13.
  • [12]Chen HC, Chen CA, Guh JY, Chang JM, Shin SJ, Lai YH. Altering expression of alpha3beta1 integrin on podocytes of human and rats with diabetes. Life Sci. 2000; 67:2345-53.
  • [13]Kreidberg JA, Donovan MJ, Goldstein SL, Rennke H, Shepherd K, Jones RC et al.. Alpha 3 beta 1 integrin has a crucial role in kidney and lung organogenesis. Development. 1996; 122:3537-47.
  • [14]Fang J, Wei H, Sun Y, Zhang X, Liu W, Chang Q et al.. Regulation of podocalyxin expression in the kidney of streptozotocin-induced diabetic rats with Chinese herbs (Yishen capsule). BMC Complement Altern Med. 2013; 13:76. BioMed Central Full Text
  • [15]Zhang J, Xie X, Li C, Fu P. Systematic review of the renal protective effect of Astragalus membranaceus (root) on diabetic nephropathy in animal models. J Ethnopharmacol. 2009; 126:189-96.
  • [16]Chang B, Jin C, Zhang W, Kong L, Yang JH, Lian FM et al.. Euonymus alatus in the treatment of diabetic nephropathy in rats. Am J Chin Med. 2012; 40:1177-87.
  • [17]Shieh JP, Cheng KC, Chung HH, Kerh YF, Yeh CH, Cheng JT. Plasma glucose lowering mechanisms of catalpol, an active principle from roots of Rehmannia glutinosa, in streptozotocin-induced diabetic rats. J Agric Food Chem. 2011; 59:3747-53.
  • [18]Zheng J, He J, Ji B, Li Y, Zhang X. Antihyperglycemic activity of Prunella vulgaris L. in streptozotocin-induced diabetic mice. Asia Pac J Clin Nutr. 2007; 16 Suppl 1:427-31.
  • [19]Valentova K, Truong NT, Moncion A, de Waziers I, Ulrichova J. Induction of glucokinase mRNA by dietary phenolic compounds in rat liver cells in vitro. J Agric Food Chem. 2007; 55:7726-31.
  • [20]Hwang SM, Kim JS, Lee YJ, Yoon JJ, Lee SM, Kang DG et al.. Anti-diabetic atherosclerosis effect of Prunella vulgaris in db/db mice with type 2 diabetes. Am J Chin Med. 2012; 40:937-51.
  • [21]Guang-Rong Z, Zhi-Jun X, Ting-Xiang Y. Antioxidant activities of Salvia miltiorrhiza and Panax notoginseng. Food Chem. 2006; 99:767-74.
  • [22]Peng SL, Guo ZA. Effect of total saponins of Panax notoginseng on urinary albumin in patients with chronic renal failure. Chinese Critical Care Medicine. 2010; 22:744-6.
  • [23]Jinxi Z, Xin M, Shidong W. Therapeutic Observations on Renal Insufficiency of Diabetic Nephropathy in Its Compensatory Phase Treated by Zhixiao Tongmai Ning Granule: A Report of 33 Cases. Henan Traditional Chinese Medicine. 2004; 24:20-2.
  • [24]Minzhou L, Yanbin G, Mingfei M. The effect of Qiwei granules on TGF-β1/Smads signaling pathway in KK-Ay mice. J Tradit Chin Med. 2013; 54:1141-4.
  • [25]Iwatsuka H, Shino A, Suzuoki Z. General survey of diabetic features of yellow KK mice. Endocrinol Jpn. 1970; 17:23-35.
  • [26]Castle CK, Colca JR, Melchior GW. Lipoprotein profile characterization of the KKA(y) mouse, a rodent model of type II diabetes, before and after treatment with the insulin-sensitizing agent pioglitazone. Arterioscler Thromb. 1993; 13:302-9.
  • [27]Okazaki M, Saito Y, Udaka Y, Maruyama M, Murakami H, Ota S et al.. Diabetic nephropathy in KK and KK-Ay mice. Exp Anim. 2002; 51:191-6.
  • [28]Xavier S, Niranjan T, Krick S, Zhang T, Ju W, Shaw AS et al.. TbetaRI independently activates Smad- and CD2AP-dependent pathways in podocytes. J Am Soc Nephrol. 2009; 20:2127-37.
  • [29]Jefferson JA, Shankland SJ, Pichler RH. Proteinuria in diabetic kidney disease: a mechanistic viewpoint. Kidney Int. 2008; 74:22-36.
  • [30]Satchell SC, Tooke JE. What is the mechanism of microalbuminuria in diabetes: a role for the glomerular endothelium? Diabetologia. 2008; 51:714-25.
  • [31]Wolf G, Chen S, Ziyadeh FN. From the periphery of the glomerular capillary wall toward the center of disease: podocyte injury comes of age in diabetic nephropathy. Diabetes. 2005; 54:1626-34.
  • [32]Aaltonen P, Luimula P, Astrom E, Palmen T, Gronholm T, Palojoki E et al.. Changes in the expression of nephrin gene and protein in experimental diabetic nephropathy. Lab Invest. 2001; 81:1185-90.
  • [33]Pozzi A, Jarad G, Moeckel GW, Coffa S, Zhang X, Gewin L et al.. Beta1 integrin expression by podocytes is required to maintain glomerular structural integrity. Dev Biol. 2008; 316:288-301.
  • [34]Huber TB, Hartleben B, Kim J, Schmidts M, Keil A, Egger L et al.. Nephrin and CD2AP associate with phosphoinositide 3-OH kinase and stimulate AKT-dependent signaling. Mol Cell Biol. 2003; 23:4917-28.
  • [35]Bridgewater DJ, Ho J, Sauro V, Matsell DG. Insulin-like growth factors inhibit podocyte apoptosis through the PI3 kinase pathway. Kidney Int. 2005; 67:1308-14.
  • [36]Tuncdemir M, Ozturk M. The effects of angiotensin-II receptor blockers on podocyte damage and glomerular apoptosis in a rat model of experimental streptozotocin-induced diabetic nephropathy. Acta Histochem. 2011; 113:826-32.
  • [37]Gui D, Guo Y, Wang F, Liu W, Chen J, Chen Y et al.. Astragaloside IV, a novel antioxidant, prevents glucose-induced podocyte apoptosis in vitro and in vivo. PLoS One. 2012; 7:e39824.
  • [38]Li C, Siragy H. High glucose induces podocyte injury via enhanced (pro)renin Receptor-Wnt-β-Catenin-Snail signaling. PLoS One. 2014; 2:e89233.
  文献评价指标  
  下载次数:149次 浏览次数:11次