Diyabetik albino Balb/c farelerde aminoguanidinin böbrek üzerindeki etkisi

Bu çalışmanın amacı, uyarılabilir nitrik oksit sentaz (iNOS) aktivasyonunun ve nitrik oksidin streptozotosin (STZ) ile uyarılmış diyabetik farelerde böbrek dokusunu nasıl etkilediğini ve etkisinin spesifik bir iNOS inhibitörü olan aminoguanidin (AG) ile önlenip önlenemediğini öğrenmektir. Yirmi dört erkek fare, 90 gün boyunca günlük 100 mg.kg-1 AG (AG Grubu), tek doz 150 mg.kg-1 STZ (STZ Grubu), tek doz 150 mg.kg-1STZ’yi takiben 90 gün boyunca günlük 100 mg.kg-1 AG (STZ-AG Grubu) ve sadece intraperitonal fizyolojik tuzlu su (Kontrol Grubu) alan dört gruba ayrılmıştır. NADPH-diaforez (NADPH-d) dağılımı, STZ uygulanmış hayvanların böbrek kesitlerinde kontrolle karşılaştırıldığında daha fazlaydı. STZ uygulaması proksimal tübüllerde fırça kenarların devamlılığının bozulmasına, glomerulus endotelinde hasara ve jukstaglomerular hücrelerde renin granüllerinin daha fazla olmasına yol açmıştır. STZ uygulamasını takiben verilen AG, böbrek korteksindeki histolojik ve sitolojik değişiklikleri kısmen önlemiştir ve renin dağılımı kontrol hayvanlardakine benzer şekilde olmuştur. Uyarılabilir nitrik oksit (iNO) artışıyla böbrekte meydana gelen bozulmanın AG uygulamasıyla kısmen önlenebildiği bulunmuştur. Diyabette, artan iNOS ile jukstaglomerular hücrelerde renin granülleri dağılımı arasında olası bir ilişki vardır.

The effect of aminoguanidine on the kidney of diabetic albino Balb/c mice

The aim of this study is to find out how activated inducible nitric oxide synthase (iNOS) and nitric oxide (NO) affect kidney tissue in streptozotocin (STZ)-induced diabetic mice and whether its influence can be prevented by aminoguanidine (AG), a specific iNOS inhibitor. Twenty-four male mice were divided into four study groups (n=6) receiving a daily dose of 100 mg.kg-1 AG for 90 days (Group AG), a single dose of 150 mg.kg-1 STZ (Group STZ), a single dose of 150 mg.kg-1 STZ followed by daily administration of 100 mg.kg-1 AG for 90 days (Group STZ-AG), and intraperitoneally injections of saline only (Group Control) for 90 days. Dispersion of NADPH-diaphorase (NADPH-d) was stronger in the kidney sections of STZ-treated animals compared with the controls. STZ treatment caused disruption of continuity of the brush borders in proximal tubules, glomerular endothelial damage, and considerable renin granules in the juxtaglomerular cells. AG administration following STZ treatment partly prevented histological and cytological changes in kidney cortex, and renin dispersion was similar to that in control animals. We found that increased inducible nitric oxide (iNO) caused kidney tissue degeneration that could be prevented to some extent by AG treatment. There is a possible relationship between increased iNOS and dispersion of renin granules in juxtaglomerular cells in diabetes.
Keywords:

-,

___

  • Atasayar S., Gürer-Orhan H., Orhan H., Gürel B., Girgin G. and Ozgüneş H. (2009) Preventive effect of aminoguanidine compared to vitamin E and C on cisplatin-induced nephrotoxicity in rats. Exp. Toxicol. Pathol., 61 (1): 23-32.
  • Azal O., Yönem A., Güler S., Cakir B., Baydar A., Corakçi A. and Kutlu M. (2002) Effects of aminoguanidine and tolrestat on the development of ocular and renal structural changes in experimental diabetic rats. Diabetes Obes. Metab., 4 (1): 75-79.
  • Bachmann S., Bosse H.M. and Mundel P. (1995) Topography of nitric oxide synthesis by localizing mammalian kidney. Am. J. Physiol., 268: F885- F898. NO synthases in
  • Birrell A.M., Heffernan S.J., Kirwan P., McLennan S., Gillin A.G. and Yue D.K. (2002) The effects of aminoguanidine on renal changes in a baboon model of Type 1 diabetes. J. Diabetes Complications, 16 (4): 301-309.
  • Bogdan C., Rollinghoff M. and Diefenbach, A. (2000) The role of nitric oxide in innate immunity. Immunol. Rev., 173: 17-26.
  • Bogdan C. (2001) Nitric oxide and the immune response. Nat. Immunol., 2 (10): 907-916.
  • Brown G.C. (1999) Nitric oxide and mitochondrial respiration. Biochim. Biophys. Acta, 1411 (2-3): 351-369.
  • Bucher M., Ittner K.P., Hobbhahn J., Taeger K. and Kurtz A. (2001) Downregulation of angiotensin II type 1 receptors during sepsis. Hypertension, 38 (2): 177-182.
  • De Vriese A.S., Stoenoiu M.S., Elger M., Devuyst O., Vanholder R., Kriz W. and Lameire N.H. (2001) dysfunction in the hydronephrotic kidney: Role of nitric oxide. Kidney Int., 60 (1): 202-210.
  • Ellis E.N. and Good B.H. (1991) Prevention of glomerular basement membrane thickening by aminoguanidine mellitus. Metabolism, 40(10): 1016-1019. experimental diabetes
  • Forstermann U., Closs E.L., Pollock J.S., Nakane M., Schwarz P., Gath I. and Kleinert H. (1994) Nitric oxide synthase isozymes. Characterization, purification, molecular cloning, and functions. Hypertension, 23: 1121-1131.
  • Fujii H., Nakamura S., Kuroda S., Yoshihara F., Nakahama H., Inenaga T., Ueda-Ishibashi H., Yutani C. and Kawano Y. (2006) Relationship between renal artery stenosis and intrarenal damage in autopsy subjects with stroke. Nephrol Dial Transplant., 21 (1): 113-119.
  • Furusu A., Miyazaki M., Abe K., Tsukasaki S., Shioshita K., Sasaki O., Miyazaki K., Ozono Y., Koji T., Harada T., Sakai H. and Kohno S. (1998) Expression of endothelial and inducible nitric glomerulonephritis. Kidney Int., 53 (6): 1760- 1768. in human
  • Heidland A., Sebekova K. and Schinzel R. (2001) Advanced glycation end products and the progressive course of renal disease. Am. J. Kidney Dis., 38 (1): 100-106.
  • Hope B.T., Michael G.J., Knigge K.M. and Vincent S.R. (1991) Neuronal NADPH diaphorase is a nitric oxide synthase. Proc. Natl. Acad. Sci. U.S.A., 88: 2811-2814.
  • Ignarro L.J. (1991) Signal transduction mechanisms involving nitric oxide. Biochem. Pharmacol., 15; 41 (4): 485-490.
  • Ignarro L.J. (1996) Physiology and pathophysiology of nitric oxide. Kidney Int. Suppl., 55: 2-5.
  • Kurtz A. (2011) Renin release: sites, mechanisms, and control. Annu. Rev. Physiol., 17(73): 377- 399.
  • Lane P. and Gross S.S. (1999). Cell signaling by nitric oxide. Semin. Nephrol., 19: 215-229.
  • Marin J. and Rodrigues-Martinez M.A. (1997) Role of vascular nitric oxide in physiological and pathological conditions. Pharmacology and Therapeutics, 75: 111-134.
  • Mauer S., Steffes M., Ellis E., Sutherland D., Brown D. and Goetz F. (1984) Structural-functional relationships in diabetic nephropathy. J. Clin. Invest., 74: 1143-1155.
  • Maxwell A.J., Tsao P.S. and Cooke J.P. (1998) Modulation of the nitric oxide synthase pathway in atherosclerosis. Exp. Physiol., 83(5): 573-584.
  • Pitcock J.A. and Hartroft P.M. (1958) The juxtaglomerular relationship to the level of plasma sodium and to the zona glomerulosa of the adrenal cortex. Am. J. Path., 34 (5): 863-864. in man and their
  • Rao V.S., Santos F.A., Silva R.M. and Teixiera M.G. (2002) Effects of nitric oxide synthase inhibitors and melatonin on the hyperglycemic response to streptozotocin in rats. Vascul. Pharmacol,. 2002 Mar;38(3): 127-130.
  • Raij L. and Baylis C. (1995) Glomerular actions of nitric oxide. Kidney Int., 48(1): 20-32.
  • Reynolds E.S. (1963) The use of lead citrate at high pH as an electron-opaque stain in electron microscopy. J. Cell Biol., 17: 208-212.
  • Schmidt H.H., Lohmann S.M. and Walter U. (1993) The nitric oxide and cGMP signal transduction system: Regulation and mechanism of action. Biochem. Biophys. Acta, 1178: 153-175.
  • Skİtt O. and Jensen B.L. (2000) Cellular and renal control of renin secretion. Odense, Southern Denmark University. http://www.uninet.edu/cin2000/conferences/OleS /OleS.html
  • Smutzer G. (2001) Research tools for nitric oxide: A wide variety of reagent are available for nitric oxide research. The Scientist, 15 (6): 23-29.
  • Soulis T., Cooper M.E., Sastra S., Thallas V., Panagiotopoulos S., Bjerrum O.J. and Jerums G. (1997) Relative contributions of advanced glycation and nitric oxide synthase inhibition to aminoguanidine-mediated diabetic rats. Diabetologia, 40(10): 1141-1151.
  • Soulis T., Sastra S., Thalla V., Mortensen S.B., Wilken M., Clausen J.T., Bjerrum O.J., Petersen H., Lau J., Jerums G., Boel E. and Cooper M.E. (1999) A novel inhibitor of advanced glycation end-product vascular hypertrophy in experimental diabetes. Diabetologia, 42(4): 472-479. mesenteric
  • Stevens R.B., Sutherland D.E., Ansite J.D., Saxena M., Rossini T.J., Levay-Young B.K., Hering B.J. and Mills C.D. (1997) Insulin down-regulates the inducible nitric oxide synthase pathway: Nitric oxide as cause and effect of diabetes? J. Immunol., 1; 159 (112): 5329-5335.
  • Sugimoto H., Shikata K., Wada J., Horiuchi S. and 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.
  • Tanaka Y., Shimizu H., Sato N., Mori M. and Shimomura spontaneous nitric oxide production in the diabetogenic Pharmacology, 50(2): 69-73. Involvement of action of streptozotocin.
  • Terada Y., Tomita K., Nonoguchi H. and Marumo F. (1992) Polymerase chain reaction localization of constitutive nitric oxide synthase and soluble guanylate microdissected rat nephron segments. J. Clin. Invest., 90: 665-669. messenger RNAs in
  • Thiemermann C. (1997) Nitric oxide and septic shock. Gen Pharmacol., 29(2): 159-166.
  • Tojo A., Welch W.J., Bremer V., Kimoto M., Kimura K., Omata M., Ogawa T., Vallance P. and Wilcox C.S. (1997) Colocalization of demethylating enzymes and NOS and functional effects of methylarginines in rat kidney. Kidney Int., 52(6): 1593-1601.
  • Veelken R., Hilgers K.F., Hartner A., Haas A., Böhmer K.P. and Sterzel B. (2000) Nitric oxide synthase isoforms and glomerular hyperfiltration in early diabetic nephropathy. J. Am. Soc. Nephrol., 11: 71-79.
  • Wagner C., Jensen B.L., Kramer B.K. and Kurtz A. (1998) Control of the renin system by local factors. Kidney Int., 67: 78-83.
  • Watson M.L. (1958) Staining of tissue sections for electron microscopy with heavy metals. J. Biophys. Biochem. Cytol., 4: 475-478.
  • Wilcox C.S. and Welch W.J. (1998) Macula densa nitric oxide synthase: Expression, regulation, and function. Kidney Int., 54 (67): 53-57.
  • Yavuz D.G., Ersöz H.O., Tuncel M., Sargon M.F., Küçükkaya B., Ahiskali R. and Akalin S. (2001) Effects of aminoguanidine on glomerular basement membrane thickness and anionic charge in a diabetic rat model. Int. J. Exp. Diabetes Res., 2 (3): 225-232.