Abstract
We attempted to clarify the effects of cyclohexenonic long-chain fatty alcohol (N-hexacosanol) on nitric oxide synthase (NOS) in streptozotocin-induced diabetic nephropathy. After induction of experimental diabetes with streptozotocin, rats were maintained for 8 weeks with or without treatment by N-hexacosanol (8 mg/kg i.p. every day). Urinary albumin excretion, blood chemistry, immunoblot analysis, and real-time polymerase chain reactions (real-time PCR) of endothelial nitric oxide synthase (eNOS), inducible NOS (iNOS), and neuronal NOS (nNOS) were investigated. Although N-hexacosanol had no effects on serum glucose or insulin level, it normalized serum creatinine and urinary albumin excretion. N-hexacosanol was found to improve the diabetes-induced alterations in the eNOS, iNOS, and nNOS protein and their mRNA levels. Histologically, N-hexacosanol inhibited the progression to glomerular sclerosis. Our data suggest that N-hexacosanol improves diabetes-induced NOS alterations in the kidney, resulting in the amelioration of diabetic nephropathy.
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References
The Diabetes Control Complications Trial Research Group (1993) The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. The Diabetes Control and Complications Trial Research Group. N Engl J Med 329:977–986. doi:10.1056/NEJM199309303291401
Tesfamariam B, Brown ML, Deykin D, Cohen RA (1990) Elevated glucose promotes generation of endothelium-derived vasoconstrictor prostanoids in rabbit aorta. J Clin Invest 85:929–932. doi:10.1172/JCI114521
Jawa A, Nachimuthu S, Pendergrass M, Asnani S, Fonseca V (2006) Impaired vascular reactivity in African-American patients with type 2 diabetes mellitus and microalbuminuria or proteinuria despite angiotensin-converting enzyme inhibitor therapy. J Clin Endocrinol Metab 91:31–35. doi:10.1210/jc.2005-1632
Haneda M, Koya D, Isono M, Kikkawa R (2003) Overview of glucose signaling in mesangial cells in diabetic nephropathy. J Am Soc Nephrol 14:1374–1382. doi:10.1097/01.ASN.0000064500.89551.76
Hoshiyama M, Li B, Yao J, Harada T, Morioka T, Oite T (2003) Effect of high glucose on nitric oxide production and endothelial nitric oxide synthase protein expression in human glomerular endothelial cells. Nephron Exp Nephrol 95:e62–e68. doi:10.1159/000073673
Huang H, Shan J, Pan XH, Wang HP, Qian LB, Xia Q (2007) Carvedilol improved diabetic rat cardiac function depending on antioxidant ability. Diabetes Res Clin Pract 75:7–13. doi:10.1016/j.diabres.2006.04.016
Koya D, Haneda M, Nakagawa H, Isshiki K, Sato H, Maeda S et al (2000) Amelioration of accelerated diabetic mesangial expansion by treatment with a PKC beta inhibitor in diabetic db/db mice, a rodent model for type 2 diabetes. FASEB J 14:439–447
Satoh I, Saito M, Kinoshita Y, Shomori K, Suzuki H, Yamada M et al (2005) Effects of cyclohexenonic long-chain fatty alcohol on diabetic rat trachea. Life Sci 77:2030–2039. doi:10.1016/j.lfs.2005.04.022
Hanada T, Saito M, Kanzaki S (2006) Treatment with cyclohexenonic long-chain fatty alcohol reverses diabetes-induced tracheal dysfunction in the rat. Pharmacology 78(2):51–60. doi:10.1159/000095120
Kinoshita Y, Saito M, Satoh I, Shomori K, Suzuki H, Yamada M et al (2006) General administration of cyclohexenonic long-chain fatty alcohol ameliorates hyperreactivity of STZ-induced diabetic rat aorta. Life Sci 78:1508–1514. doi:10.1016/j.lfs.2005.07.043
Shinbori C, Saito M, Kinoshita Y, Satoh I, Kono T, Hanada T et al (2007) Cyclohexenonic long-chain fatty alcohol has therapeutic effects on diabetes-induced angiopathy in the rat aorta. Eur J Pharmacol 567:139–144. doi:10.1016/j.ejphar.2007.04.009
Suzuki H, Saito M, Kinoshita Y, Satoh I, Kono T, ShinBori C, Anastasios S, Yamada M, Satoh K (2006) Preventive effects of cyclohexenonic long-chain fatty alcohol on diabetic cystopathy in the rat. Can J Physiol Pharmacol 84(2):195–201. doi:10.1139/y05-114
Saito M, Kinoshita Y, Satoh I, Shinbori C, Suzuki H, Yamada M et al (2007) Ability of cyclohexenonic long-chain Fatty alcohol to reverse diabetes-induced cystopathy in the rat. Eur Urol 51:479–488. doi:10.1016/j.eururo.2006.06.024
Saito M, Kinoshita Y, Satoh I, Shinbori C, Kono T, Hanada T et al (2006) N-hexacosanol ameliorates streptozotocin-induced diabetic rat nephropathy. Eur J Pharmacol 544:132–137. doi:10.1016/j.ejphar.2006.06.001
Li B, Yao J, Kawamura K, Oyanagi Tanaka Y, Hoshiyama M, Morioka T et al (2004) Real-time observation of glomerular hemodynamic changes in diabetic rats: effects of insulin and ARB. Kidney Int 66:1939–1948. doi:10.1111/j.1523-1755.2004.00979.x
Raij L, Azar S, Keane W (1984) Mesangial immune injury, hypertension, and progressive glomerular damage in Dahl rats. Kidney Int 26:137–143. doi:10.1038/ki.1984.147
Fujihara CK, Mattar AL, Vieira JM Jr, Malheiros DM, Noronha Ide L, Goncalves AR et al (2002) Evidence for the existence of two distinct functions for the inducible NO synthase in the rat kidney: effect of aminoguanidine in rats with 5/6 ablation. J Am Soc Nephrol 13:2278–2287. doi:10.1097/01.ASN.0000027354.12330.F4
Soong R, Beyser K, Basten O, Kalbe A, Rueschoff J, Tabiti K (2001) Quantitative reverse transcription-polymerase chain reaction detection of cytokeratin 20 in noncolorectal lymph nodes. Clin Cancer Res 7:3423–3429
Kono T, Saito M, Kinoshita Y, Satoh I, Shinbori C, Satoh K (2006) Real-time monitoring of nitric oxide and blood flow during ischemia-reperfusion in the rat testis. Mol Cell Biochem 286(1–2):139–145. doi:10.1007/s11010-005-9105-3
Raij L, Baylis C (1995) Glomerular actions of nitric oxide. Kidney Int 48:20–32. doi:10.1038/ki.1995.262
Roczniak A, Burns KD (1996) Nitric oxide stimulates guanylate cyclase and regulates sodium transport in rabbit proximal tubule. Am J Physiol 270:F106–F115
McKee M, Scavone C, Nathanson JA (1994) Nitric oxide, cGMP, and hormone regulation of active sodium transport. Proc Natl Acad Sci USA 91:12056–12060. doi:10.1073/pnas.91.25.12056
Stoos BA, Garcia NH, Garvin JL (1995) Nitric oxide inhibits sodium reabsorption in the isolated perfused cortical collecting duct. J Am Soc Nephrol 6:89–94. doi:10.1159/000106927
Majid DS, Williams A, Navar LG (1993) Inhibition of nitric oxide synthesis attenuates pressure-induced natriuretic responses in anesthetized dogs. Am J Physiol 264:F79–F87
Fenoy FJ, Ferrer P, Carbonell L, Garcia-Salom M (1995) Role of nitric oxide on papillary blood flow and pressure natriuresis. Hypertension 25:408–414
Sugimoto H, Shikata K, Matsuda M, Kushiro M, Hayashi Y, Hiragushi K et al (1998) Increased expression of endothelial cell nitric oxide synthase (ecNOS) in afferent and glomerular endothelial cells is involved in glomerular hyperfiltration of diabetic nephropathy. Diabetologia 41(12):1426–1434. doi:10.1007/s001250051088
Veelken R, Hilgers KF, Hartner A, Haas A, Bohmer KP, Sterzel RB (2000) Nitric oxide synthase isoforms and glomerular hyperfiltration in early diabetic nephropathy. J Am Soc Nephrol 11(1):71–79
Choi KC, Kim NH, An MR, Kang DG, Kim SW, Lee J (1997) Alterations of intrarenal renin–angiotensin and nitric oxide systems in streptozotocin-induced diabetic rats. Kidney Int Suppl 60:S23–S27
De Vriese AS, Stoenoiu MS, Elger M, Devuyst O, Vanholder R, Kriz W et al (2001) Diabetes-induced microvascular dysfunction in the hydronephrotic kidney: role of nitric oxide. Kidney Int 60(1):202–210. doi:10.1046/j.1523-1755.2001.00787.x
Onozato ML, Tojo A, Goto A, Fujita T, Wilcox CS (2002) Oxidative stress and nitric oxide synthase in rat diabetic nephropathy: effects of ACEI and ARB. Kidney Int 61(1):186–194. doi:10.1046/j.1523-1755.2002.00123.x
Khamaisi M, Keynan S, Bursztyn M, Dahan R, Reinhartz E, Ovadia H et al (2006) Role of renal nitric oxide synthase in diabetic kidney disease during the chronic phase of diabetes. Nephron Physiol 102(3–4):72–80. doi:10.1159/000089946
Keynan S, Hirshberg B, Levin Iaina N, Wexler ID, Dahan R, Reinhartz E et al (2000) Renal nitric oxide production during the early phase of experimental diabetes mellitus. Kidney Int 58(2):740–747. doi:10.1046/j.1523-1755.2000.00220.x
Ishii N, Patel KP, Lane PH, Taylor T, Bian K, Murad F et al (2001) Nitric oxide synthesis and oxidative stress in the renal cortex of rats with diabetes mellitus. J Am Soc Nephrol 12(8):1630–1639
Shin SJ, Lai FJ, Wen JD, Hsiao PJ, Hsieh MC, Tzeng TF et al (2000) Neuronal and endothelial nitric oxide synthase expression in outer medulla of streptozotocin-induced diabetic rat kidney. Diabetologia 43(5):649–659. doi:10.1007/s001250051354
Schwartz D, Schwartz IF, Blantz RC (2001) An analysis of renal nitric oxide contribution to hyperfiltration in diabetic rats. J Lab Clin Med 137(2):107–114. doi:10.1067/mlc.2001.112691
Sugimoto H, Shikata K, Wada J, Horiuchi S, Makino H (1999) Advanced glycation end products-cytokine-nitric oxide sequence pathway in the development of diabetic nephropathy: aminoguanidine ameliorates the overexpression of tumour necrosis factor-alpha and inducible nitric oxide synthase in diabetic rat glomeruli. Diabetologia 42(7):878–886. doi:10.1007/s001250051241
Soulis T, Cooper ME, Sastra S, Thallas V, Panagiotopoulos S, Bjerrum OJ et al (1997) Relative contributions of advanced glycation and nitric oxide synthase inhibition to aminoguanidine-mediated renoprotection in diabetic rats. Diabetologia 40(10):1141–1151. doi:10.1007/s001250050799
Komers R, Lindsley JN, Oyama TT, Anderson S (2004) Effects of long-term inhibition of neuronal nitric oxide synthase (NOS1) in uninephrectomized diabetic rats. Nitric Oxide 11:147–155. doi:10.1016/j.niox.2004.08.005
Yabuki A, Tahara T, Taniguchi K, Matsumoto M, Suzuki S (2006) Neuronal nitric oxide synthase and cyclooxygenase-2 in diabetic nephropathy of type 2 diabetic OLETF rats. Exp Anim 55:17–25. doi:10.1538/expanim.55.17
Shin SJ, Lai FJ, Wen JD, Lin SR, Hsieh MC, Hsiao PJ et al (1999) Increased nitric oxide synthase mRNA expression in the renal medulla of water-deprived rats. Kidney Int 56:2191–2202. doi:10.1046/j.1523-1755.1999.00795.x
Trujillo J, Ramirez V, Perez J, Torre-Villalvazo I, Torres N, Tovar AR et al (2005) Renal protection by a soy diet in obese Zucker rats is associated with restoration of nitric oxide generation. Am J Physiol Renal Physiol 288:F108–F116. doi:10.1152/ajprenal.00077.2004
Kuboki K, Jiang ZY, Takahara N, Ha SW, Igarashi M, Yamauchi T et al (2000) Regulation of endothelial constitutive nitric oxide synthase gene expression in endothelial cells and in vivo: a specific vascular action of insulin. Circulation 101(6):676–681
Ishizaki M, Masuda Y, Fukuda Y, Sugisaki Y, Yamanaka N, Masugi Y (1986) Experimental mesangioproliferative glomerulonephritis in rats induced by intravenous administration of anti-thymocyte serum. Acta Pathol Jpn 36:1191–1203
Yamagishi S, Inagaki Y, Okamoto T, Amano S, Koga K, Takeuchi M (2003) Advanced glycation end products inhibit de novo protein synthesis and induce TGF-beta overexpression in proximal tubular cells. Kidney Int 63:464–473. doi:10.1046/j.1523-1755.2003.00752.x
Satoh M, Fujimoto S, Haruna Y, Arakawa S, Horike H, Komai N et al (2005) NAD(P)H oxidase and uncoupled nitric oxide synthase are major sources of glomerular superoxide in rats with experimental diabetic nephropathy. Am J Physiol Renal Physiol 288:F1144–F1152. doi:10.1152/ajprenal.00221.2004
Saito M, Suzuki H, Yamada M, Miyagawa I (2002) Preventive effect of long-chain fatty alcohol on ischemia—reperfusion injury in the rat bladder. Eur J Pharmacol 454:81–84. doi:10.1016/S0014-2999(02)02471-8
Acknowledgments
This study was supported in part by the Morinaga Houshikai Research Foundation. We gratefully acknowledge Dr. Y. Kinoshita and I. Satoh, Division of Molecular Pharmacology, Tottori University, Japan, for their technical assistance.
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Okada, S., Saito, M., Kazuyama, E. et al. Effects of N-hexacosanol on nitric oxide synthase system in diabetic rat nephropathy. Mol Cell Biochem 315, 169–177 (2008). https://doi.org/10.1007/s11010-008-9804-7
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DOI: https://doi.org/10.1007/s11010-008-9804-7