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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.

[1]Basta, G., 2008. Receptor for advanced glycation endproducts and atherosclerosis: from basic mechanisms to clinical implications. Atherosclerosis, 196(1):9-21.

[2]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.

[3]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.

[4]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.

[5]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.

[6]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.

[7]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.

[8]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.

[9]Fried, L.F., Orchard, T.J., Kasiske, B.L., 2001. Effect of lipid reduction on the progression of renal disease: a meta-analysis. Kidney Int., 59(1):260-269.

[10]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.

[11]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.

[12]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.

[13]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.

[14]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.

[15]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.

[16]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.

[17]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.

[18]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.

[19]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.

[20]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.

[21]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.

[22]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.

[23]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.

[24]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.

[25]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.

[26]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.

[27]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.

[28]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.

[29]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.

[30]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.

[31]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.

[32]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.

[33]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.

[34]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.