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Effects of atorvastatin on progression of diabetic nephropathy and local RAGE and soluble RAGE expressions in rats

Journal of Zhejiang University SCIENCE B volume 12, pages 652–659 (2011)Cite this article

Abstract

Objective

Advanced glycation end-products (AGEs) exert inflammatory and oxidative stress insults to produce diabetic nephropathy mainly through the receptor for AGEs (RAGE). This study aimed to assess the effect of atorvastatin on diabetic nephropathy via soluble RAGE (sRAGE) and RAGE expressions in the rat kidney.

Methods

Thirty-two male Sprague-Dawley rats were divided into four groups based on the presence or absence of streptozotocin-induced diabetes with or without atorvastatin treatment (10 mg/kg for 24 weeks). Serum sRAGE and glycated albumin (GA) levels were measured with enzyme-linked immunosorbent assay (ELISA) and improved bromocresol purple methods. Renal AGEs, RAGE, endogenous secretory RAGE (esRAGE), and sRAGE were determined with reverse transcription-polymerase chain reaction (RT-PCR) and Western blotting.

Results

Mesangial expansion and microalbuminuria were aggravated in diabetic rats, and improved with atorvastatin treatment. Serum sRAGE levels were lower in diabetic than in normal rats. After atorvastatin treatment, serum and renal sRAGE levels were up-regulated, while renal RAGE expression was decreased in diabetic rats, associated with a reduction in accumulation of AGEs, though renal esRAGE mRNA expression was not significantly increased.

Conclusions

Atorvastatin exerted a beneficial effect on diabetic nephropathy with reduced AGE accumulation, down-regulating RAGE expression and up-regulating sRAGE in the kidney.

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References

  • Basta, G., 2008. Receptor for advanced glycation endproducts and atherosclerosis: from basic mechanisms to clinical implications. Atherosclerosis, 196(1):9–21. [doi:10.1016/j.atherosclero sis.2007.07.025]

    Article  PubMed  CAS  Google Scholar 

  • Bohlender, J.M., Franke, S., Stein, G., Wolf, G., 2005. Advanced glycation end products and the kidney. Am. J. Physiol. Renal. Physiol., 289(4):F645–F659. [doi:10.1152/ajprenal.00398.2004]

    Article  PubMed  CAS  Google Scholar 

  • Cohen, M.P., Ziyadeh, F.N., 1996. Role of Amadori-modified nonenzymatically glycated serum proteins in the pathogenesis of diabetic nephropathy. J. Am. Soc. Nephrol., 7(2):183–190.

    PubMed  CAS  Google Scholar 

  • Cohen, M.P., Ziyadeh, F.N., Chen, S., 2006. Amadori-modified glycated serum proteins and accelerated atherosclerosis in diabetes: pathogenic and therapeutic implications. J. Lab. Clin. Med., 147(5):211–219. [doi:10.1016/j.la b.2005.12.006]

    Article  PubMed  CAS  Google Scholar 

  • Cuccurullo, C., Iezzi, A., Fazia, M.L., de Cesare, D., di Francesco, A., Muraro, R., Bei, R., Ucchino, S., Spigonardo, F., Chiarelli, F., et al., 2006. Suppression of RAGE as a basis of simvastatin-dependent plaque stabilization in type 2 diabetes. Arterioscler. Thromb. Vasc. Biol., 26(12): 2716–2723. [doi:10.1161/01.ATV.0000249630.02085.12]

    Article  PubMed  CAS  Google Scholar 

  • Devangelio, E., Santilli, F., Formoso, G., Ferroni, P., Bucciarelli, L., Michetti, N., Clissa, C., Ciabattoni, G., Consoli, A., Davi, G., 2007. Soluble RAGE in type 2 diabetes: association with oxidative stress. Free Radic. Biol. Med., 43(4):511–518. [doi:10.1016/j.freeradbiomed.2007.03.015]

    Article  PubMed  CAS  Google Scholar 

  • Flyvbjerg, A., Denner, L., Schrijvers, B.F., Tilton, R.G., Mogensen, T.H., Paludan, S.R., Rasch, R., 2004. Long-term renal effects of a neutralizing RAGE antibody in obese type 2 diabetic mice. Diabetes, 53(1):166–172. [doi:10.2337/diabetes.53.1.166]

    Article  PubMed  CAS  Google Scholar 

  • Forbes, J.M., Thorpe, S.R., Thallas-Bonke, V., Pete, J., Thomas, M.C., Deemer, E.R., Bassal, S., El-Osta, A., Long, D.M., Panagiotopoulos, S., et al., 2005. Modulation of soluble receptor for advanced glycation end products by angiotensin-converting enzyme-1 inhibition in diabetic nephropathy. J. Am. Soc. Nephrol., 16(8):2363–2372. [doi:10.1681/ASN.2005010062]

    Article  PubMed  CAS  Google Scholar 

  • Fried, L.F., Orchard, T.J., Kasiske, B.L., 2001. Effect of lipid reduction on the progression of renal disease: a metaanalysis. Kidney Int., 59(1):260–269. [doi:10.1046/j.1523-1755.2001.00487.x]

    Article  PubMed  CAS  Google Scholar 

  • Gohda, T., Tanimoto, M., Moon, J.Y., Gotoh, H., Aoki, T., Matsumoto, M., Shibata, T., Ohsawa, I., Funabiki, K., Tomino, Y., 2008. Increased serum endogenous secretory receptor for advanced glycation end-product (esRAGE) levels in type 2 diabetic patients with decreased renal function. Diabetes Res. Clin. Pract., 81(2):196–201. [doi:10.1016/j.diabres.2008.04.013]

    Article  PubMed  CAS  Google Scholar 

  • Goldin, A., Beckman, J.A., Schmidt, A.M., Creager, M.A., 2006. Advanced glycation end products: sparking the development of diabetic vascular injury. Circulation, 114(6):597–605. [doi:10.1161/CIRCULATIONAHA.106.621854]

    Article  PubMed  CAS  Google Scholar 

  • Harashima, A., Yamamoto, Y., Cheng, C., Tsuneyama, K., Myint, K.M., Takeuchi, A., Yoshimura, K., Li, H., Watanabe, T., Takasawa, S., et al., 2006. Identification of mouse orthologue of endogenous secretory receptor for advanced glycation end-products: structure, function and expression. Biochem. J., 396(1):109–115. [doi:10.1042/BJ20051573]

    Article  PubMed  CAS  Google Scholar 

  • Hudson, B.I., Harja, E., Moser, B., Schmidt, A.M., 2005. Soluble levels of receptor for advanced glycation endproducts (sRAGE) and coronary artery disease: the next C-reactive protein? Arterioscler. Thromb. Vasc. Biol., 25(5): 879–882. [doi:10.1161/01.ATV.0000164804.05324.8b]

    Article  CAS  Google Scholar 

  • Humpert, P.M., Djuric, Z., Kopf, S., Rudofsky, G., Morcos, M., Nawroth, P.P., Bierhaus, A., 2007. Soluble RAGE but not endogenous secretory RAGE is associated with albuminuria in patients with type 2 diabetes. Cardiovasc. Diabetol., 6(1):9. [doi:10.1186/1475-2840-6-9]

    Article  PubMed  Google Scholar 

  • Kasiske, B.L., O’Donnell, M.P., Cleary, M.P., Keane, W.F., 1988. Treatment of hyperlipidemia reduces glomerular injury in obese Zucker rats. Kidney Int., 33(3):667–672. [doi:10.1038/ki.1988.51]

    Article  PubMed  CAS  Google Scholar 

  • Koyama, H., Shoji, T., Fukumoto, S., Shinohara, K., Shoji, T., Emoto, M., Mori, K., Tahara, H., Ishimura, E., Kakiya, R., et al., 2007. Low circulating endogenous secretory receptor for AGEs predicts cardiovascular mortality in patients with end-stage renal disease. Arterioscler. Thromb. Vasc. Biol., 27(1):147–153. [doi:10.1161/01.ATV.0000251502.88818.4b]

    Article  PubMed  CAS  Google Scholar 

  • Kurusu, A., Shou, I., Nakamura, S., Fukui, M., Shirato, I., Tomino, Y., 2000. Effects of the new hydroxy 3-methylglutaryl coenzyme a reductase inhibitor fluvastatin on anti-oxidant enzyme activities and renal function in streptozotocin-induced diabetic rats. Clin. Exp. Pharmacol. Physiol., 27(10):767–770. [doi:10.1046/j.1440-1681.2000.03335.x]

    Article  PubMed  CAS  Google Scholar 

  • Lu, L., Pu, L.J., Xu, X.W., Zhang, Q., Zhang, R.Y., Zhang, J.S., Hu, J., Yang, Z.K., Lu, A.K., Ding, F.H., et al., 2007. Association of serum levels of glycated albumin, C-reactive protein and tumor necrosis factor-α with the severity of coronary artery disease and renal impairment in patients with type 2 diabetes mellitus. Clin. Biochem., 40(11):810–816. [doi:10.1016/j.clinbiochem.2007.03.022]

    Article  PubMed  CAS  Google Scholar 

  • Lu, L., Zhang, Q., Pu, L.J., Peng, W.H., Yan, X.X., Wang, L.J., Chen, Q.J., Zhu, Z.B., Michel, J.B., Shen, W.F., 2008. Dysregulation of matrix metalloproteinases and their tissue inhibitors is related to abnormality of left ventricular geometry and function in streptozotocin-induced diabetic minipigs. Int. J. Exp. Pathol., 89(2):125–137. [doi:10.1111/j.1365-2613.2008.00579.x]

    Article  PubMed  CAS  Google Scholar 

  • Nakamura, K., Yamagishi, S., Adachi, H., Matsui, T., Kurita-Nakamura, Y., Takeuchi, M., Inoue, H., Imaizumi, T., 2008. Serum levels of soluble form of receptor for advanced glycation end products (sRAGE) are positively associated with circulating AGEs and soluble form of VCAM-1 in patients with type 2 diabetes. Microvasc. Res., 76(1):52–56. [doi:10.1016/j.mvr.2007.09.004]

    Article  PubMed  CAS  Google Scholar 

  • Nishizawa, Y., Koyama, H., 2008. Endogenous secretory receptor for advanced glycation end-products and cardiovascular disease in end-stage renal disease. J. Ren. Nutr., 18(1):76–82. [doi:10.1053/j.jrn.2007.10.016]

    Article  PubMed  Google Scholar 

  • O’Donnell, M.P., Kasiske, B.L., Kim, Y., Schmitz, P.G., Keane, W.F., 1993. Lovastatin retards the progression of established glomerular disease in obese Zucker rats. Am. J. Kidney Dis., 22(1):83–89.

    PubMed  Google Scholar 

  • Pu, L.J., Lu, L., Shen, W.F., Zhang, Q., Zhang, R.Y., Zhang, J.S., Hu, J., Yang, Z.K., Ding, F.H., Chen, Q.J., et al., 2007. Increased serum glycated albumin level is associated with the presence and severity of coronary artery disease in type 2 diabetic patients. Circ. J., 71(7): 1067–1073. [doi:10.1253/circj.71.1067]

    Article  PubMed  CAS  Google Scholar 

  • Radaelli, A., Loardi, C., Cazzaniga, M., Balestri, G., DeCarlini, C., Cerrito, M.G., Cusa, E.N., Guerra, L., Garducci, S., Santo, D., et al., 2007. Inflammatory activation during coronary artery surgery and its dose-dependent modulation by statin/ACE-inhibitor combination. Arterioscler. Thromb. Vasc. Biol., 27(12):2750–2755. [doi:10.1161/ATVBAHA.107.149039]

    Article  PubMed  CAS  Google Scholar 

  • Sandhu, S., Wiebe, N., Fried, L.F., Tonelli, M., 2006. Statins for improving renal outcomes: a meta-analysis. J. Am. Soc. Nephrol., 17(7):2006–2016. [doi:10.1681/ASN.2006010012]

    Article  PubMed  CAS  Google Scholar 

  • Santilli, F., Vazzana, N., Bucciarelli, L.G., Davi, G., 2009. Soluble forms of RAGE in human diseases: clinical and therapeutical implications. Curr. Med. Chem., 16(8): 940–952. [doi:10.2174/092986709787581888]

    Article  PubMed  CAS  Google Scholar 

  • Sugaya, K., Fukagawa, T., Matsumoto, K., Mita, K., Takahashi, E., Ando, A., Inoko, H., Ikemura, T., 1994. Three genes in human MHC class III region near the junction with the class II: gene for receptor of advanced glycosylation end products, PBX2 homeobox gene and a notch homolog, human counterpart of mouse mammary tumor gene int-3. Genomics, 23(2):408–419. [doi:10.1006/geno.1994.1517]

    Article  PubMed  CAS  Google Scholar 

  • Tan, K.C., Shiu, S.W., Chow, W.S., Leng, L., Bucala, R., Betteridge, D.J., 2006. Association between serum levels of soluble receptor for advanced glycation end products and circulating advanced glycation end products in type 2 diabetes. Diabetologia, 49(11):2756–2762. [doi:10.1007/s00125-006-0394-1]

    Article  PubMed  CAS  Google Scholar 

  • Tan, K.C., Chow, W.S., Tso, A.W., Xu, A., Tse, H.F., Hoo, R.L., Betteridge, D.J., Lam, K.S., 2007. Thiazolidinedione increases serum soluble receptor for advanced glycation end-products in type 2 diabetes. Diabetologia, 50(9):1819–1825. [doi:10.1007/s00125-007-0759-0]

    Article  PubMed  CAS  Google Scholar 

  • Thallas-Bonke, V., Lindschau, C., Rizkalla, B., Bach, L.A., Boner, G., Meier, M., Haller, H., Cooper, M.E., Forbes, J.M., 2004. Attenuation of extracellular matrix accumulation in diabetic nephropathy by the advanced glycation end product cross-link breaker ALT-711 via a protein kinase C-α-dependent pathway. Diabetes, 53(11): 2921–2930. [doi:10.2337/diabetes.53.11.2921]

    Article  PubMed  CAS  Google Scholar 

  • van Linthout, S., Spillmann, F., Riad, A., Trimpert, C., Lievens, J., Meloni, M., Escher, F., Filenberg, E., Demir, O., Li, J., et al., 2008. Human apolipoprotein A-I gene transfer reduces the development of experimental diabetic cardiomyopathy. Circulation, 117(12):1563–1573. [doi:10.1161/CIRCULATIONAHA.107.710830]

    Article  PubMed  Google Scholar 

  • Wendt, T.M., Tanji, N., Guo, J., Kislinger, T.R., Qu, W., Lu, Y., Bucciarelli, L.G., Rong, L.L., Moser, B., Markowitz, G.S., et al., 2003. RAGE drives the development of glomerulosclerosis and implicates podocyte activation in the pathogenesis of diabetic nephropathy. Am. J. Pathol., 162(4):1123–1137. [doi:10.1016/S0002-9440(10)63909-0]

    Article  PubMed  CAS  Google Scholar 

  • Wilkinson-Berka, J.L., Kelly, D.J., Koemer, S.M., Jaworski, K., Davis, B., Thallas, V., Cooper, M.E., 2002. ALT-946 and aminoguanidine, inhibitors of advanced glycation, improve severe nephropathy in the diabetic transgenic (mREN-2)27 rat. Diabetes, 51(11):3283–3289. [doi:10.2337/diabetes.51.11.3283]

    Article  PubMed  CAS  Google Scholar 

  • Yan, X.X., Lu, L., Peng, W.H., Wang, L.J., Zhang, Q., Zhang, R.Y., Chen, Q.J., Shen, W.F., 2009. Increased serum HMGB1 level is associated with coronary artery disease in nondiabetic and type 2 diabetic patients. Atherosclerosis, 205(2):544–548. [doi:10.1016/j.atherosclerosis.2008.12.016]

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Cardiology, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200025, China

    Lin Lu, Wen-hui Peng, Wei Wang & Wei-feng Shen

  2. Institute of Cardiovascular Diseases, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200025, China

    Lin Lu, Wen-hui Peng, Ling-jie Wang, Qiu-jing Chen & Wei-feng Shen

Authors
  1. Lin Lu
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  2. Wen-hui Peng
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  3. Wei Wang
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  4. Ling-jie Wang
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  5. Qiu-jing Chen
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  6. Wei-feng Shen
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Correspondence to Wei-feng Shen.

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The two authors contributed equally to this work References

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Lu, L., Peng, Wh., Wang, W. et al. Effects of atorvastatin on progression of diabetic nephropathy and local RAGE and soluble RAGE expressions in rats. J. Zhejiang Univ. Sci. B 12, 652–659 (2011). https://doi.org/10.1631/jzus.B1101004

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  • DOI: https://doi.org/10.1631/jzus.B1101004

Key words

  • Receptor for advanced glycation end-product (RAGE)
  • Endogenous secretory RAGE (esRAGE)
  • Soluble RAGE (sRAGE)
  • Diabetic nephropathy
  • Atorvastatin

CLC number

  • R587.2
  • R961