1. bookVolume 67 (2017): Issue 3 (September 2017)
Journal Details
License
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Journal
eISSN
1820-7448
First Published
25 Mar 2014
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4 times per year
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English
access type Open Access

Effects of Losartan, Tempol, and Their Combination On Renal Nitric Oxide Synthases in the Animal Model of Chronic Kidney Disease

Published Online: 23 Sep 2017
Volume & Issue: Volume 67 (2017) - Issue 3 (September 2017)
Page range: 409 - 425
Received: 12 Dec 2016
Accepted: 26 May 2017
Journal Details
License
Format
Journal
eISSN
1820-7448
First Published
25 Mar 2014
Publication timeframe
4 times per year
Languages
English
Abstract

Down-regulation of nitric oxide synthase (NOS) and NO deficiency in the kidneys have been implicated in the pathogenesis of chronic kidney disease (CKD). In this study we examined the effects of losartan, tempol, and combined treatment on three NOS isoforms expressions, kidney NO content and NOS correlation with renal function and structure in the early stage of adriamycin (ADR)-induced CKD in spontaneously hypertensive rats (SHR). Rats were divided into control group, and four other groups which were treated with ADR and received vehicle, losartan (L, angiotensin II type 1 receptor blocker), tempol (T, redox-cycling nitroxide) or T+L treatment (by gavage) in a six-week study. Reduction of all NOS isoforms expressions were significantly improved by losartan or tempol, and correlated with proteinuria amelioration. Combined treatment induced down-regulation of constitutive NOS isoforms, whilst inducible NOS was up-regulated and followed by increased nitrite content and a significant decline in the glomerular filtration rate. Losartan or tempol prevented ADR-induced neoexpression of vimentin in the glomeruli and tubulointerstital areas, whereas de novo vimentin expression was still observed in the atrophic tubules and in the interstitial fibroblasts and myofibroblasts in combined treatment. It can be concluded that single treatments, contrary to combined, were effective in improving NO bioavailability and slowing down the progression of CKD.

Keywords

1. Andrew PJ, Mayer B: Enzymatic function of nitric oxide synthases. Cardiovasc. Res. 1999, 43:521-531.10.1016/S0008-6363(99)00115-7Search in Google Scholar

2. Raij L, Baylis C: Glomerular actions of nitric oxide. Kidney Int. 1995, 48:20-32.10.1038/ki.1995.2627564080Search in Google Scholar

3. Baylis C, Mitruka B, Deng A: Chronic blockade of nitric oxide synthesis in the rat produces systemic hypertension and glomerular damage. J. Clin. Invest. 1992, 90:278-281.10.1172/JCI1158494430931634615Search in Google Scholar

4. Furusu A, Miyazaki M, Abe K, Tsukasaki S, Shioshita K, Sasaki O, Miyazaki K, Ozono Y, Koji T, Harada T, Sakai H, Kohno S: Expression of endothelial and inducible nitric oxide synthase in human glomerulonephritis. Kidney Int. 1998, 53:1760-1768.10.1046/j.1523-1755.1998.00907.x9607210Search in Google Scholar

5. Vaziri ND, Ni Z, Oveisi F, Liang K, Pandian R: Enhanced nitric oxide inactivation and protein nitration by reactive oxygen species in renal insufficiency. Hypertension 2002, 39:135-141.10.1161/hy0102.10054011799092Search in Google Scholar

6. Bachmann S, Bosse HM, Mundel P: Topography of nitric oxide synthesis by localizing constitutive NO synthases in mammalian kidney. Am J Physiol 1995, 268:F885-F897.10.1152/ajprenal.1995.268.5.F8857539586Search in Google Scholar

7. Ashab I, Peer G, Blum M, Wollman Y, Chernihovsky T, Hassner A, Schwartz D, Cabili S, Silverberg D, Iaina A: Oral administration of L-arginine and captopril in rats prevents chronic renal failure by nitric oxide production. Kidney Int. 1995, 47:1515-1521.10.1038/ki.1995.2147643519Search in Google Scholar

8. Aiello S, Noris M, Todeschini M, Zappella S, Foglieni C, Benigni A, Corna D, Zoja C, Cavallotti D, Remuzzi G: Renal and systemic nitric oxide synthesis in rats with renal mass reduction. Kidney Int. 1997, 52:171-181.10.1038/ki.1997.3179211360Search in Google Scholar

9. Mazroa SA, Asker SA, El-Shafey S: Immunohistochemical Distribution of Inducible Nitric Oxide Synthase Enzyme ( iNOS ) in the Renal Cortex of Control and Diabetic Adult Male Albino Rats and the Effect of iNOS Inhibition by Aminoguanidine. Egypt. J. Histol. 2009, 32:235-45.Search in Google Scholar

10. Baylis C: Nitric oxide synthase derangements and hypertension in kidney disease. Curr. Opin. Nephrol. Hypertens. 2012, 21:1-6.10.1097/MNH.0b013e32834d54ca327793422048724Search in Google Scholar

11. Sun YBY, Qu X, Zhang X, Caruana G, Bertram JF, Li: Glomerular endothelial cell injury and damage precedes that of podocytes in adriamycin-induced nephropathy. PLoS One 2013, 8:1-12.10.1371/journal.pone.0055027355467023359116Search in Google Scholar

12. Rangan GK, Wang Y, Harris DCH: Pharmacologic modulators of nitric oxide exacerbate tubulointerstitial inflammation in proteinuric rats. J Am Soc Nephrol. 2001, 12:1696-1705.10.1681/ASN.V128169611461942Search in Google Scholar

13. Muller V, Tain YL, Croker B, Baylis C: Chronic nitric oxide defi ciency and progression of kidney disease after renal mass reduction in the C57Bl6 mouse. Am J Nephrol. 2010, 32(6):575-80.10.1159/000322106299265121071934Search in Google Scholar

14. Nakagawa T, Sato W, Glushakova O, Heinig M, Clarke T, Campbell-Thompson M, Yuzawa Y, Atkinson MA, Johnson RJ, Croker B: Diabetic endothelial nitric oxide synthase knockout mice develop advanced diabetic nephropathy. J Am Soc Nephrol. 2007, 18:539-550.10.1681/ASN.200605045917202420Search in Google Scholar

15. Kashiwagi M, Shinozaki M, Hirakata H, Tamaki K, Hirano T, Tokumoto M, Goto H, Okuda S, Fujishima M: Locally activated renin-angiotensin system associated with TGF-b1 as a major factor for renal injury induced by chronic inhibition of nitric oxide synthase in rats. J Am Soc Nephrol. 2000, 11:616-624.10.1681/ASN.V11461610752520Search in Google Scholar

16. Roczniak A, Fryer JN, Levine DZ, Burns KD: Downregulation of neuronal nitric oxide synthase in the rat remnant kidney. J Am Soc Nephrol. 1999, 10:704-713.10.1681/ASN.V10470410203353Search in Google Scholar

17. Tain ZL, Freshour G, Dikalova A, Griendling K, Baylis C: Vitamin E reduces glomerulosclerosis, restores renal neuronal NOS, and suppresses oxidative stress in the 5/6 nephrectomized rat. Am. J. Physiol. Renal Physiol. 2007, 292:F1404-F1410.10.1152/ajprenal.00260.200617200156Search in Google Scholar

18. Mendoza MGA, Castillo-Henkel C, Medina-Santillan R, Jarillo Luna RA, Robles HV, Romo E, Rios A, Escalante B: Kidney damage after renal ablation is worsened in endothelial nitric oxide synthase (-/-) mice and improved by combined administration of L-arginine and antioxidants. Nephrology 2008, 13:218-27.10.1111/j.1440-1797.2007.00897.x18315704Search in Google Scholar

19. Wilcox CS: Effects of tempol and redox-cycling nitroxides in models of oxidative stress. Pharmacol. Ther. 2010, 126:119-145.10.1016/j.pharmthera.2010.01.003285432320153367Search in Google Scholar

20. Roson MI, Della Penna SL, Cao G, Gorzalczany S, Pandolfo M, Toblli JE, Fernandez BE: Different protective actions of losartan and tempol on the renal inflammatory response to acute sodium overload. J. Cell. Physiol. 2010, 224:41-48.10.1002/jcp.2208720232302Search in Google Scholar

21. Jovanovic DB, Jovovic D, Varagic J, Dimitrijevic J, Dragojlovic Z, Djukanovic L: Slowing the progression of chronic renal insuffi ciency with captopril in rats with spontaneous arterial hypertension and adriamycin nephropathy. Srp Arh Celok Lek 2002, 130:73-80.10.2298/SARH0204073J12154518Search in Google Scholar

22. Mihailović-Stanojević N, Jovović D, Miloradović Z, Grujić-Milanović J, Jerkić M, Marković-Lipkovski J: Reduced progression of adriamycin nephropathy in spontaneously hypertensive rats treated by losartan. Nephrol Dial Transplant 2009, 24:1142-50.Search in Google Scholar

23. Karanovic D, Grujic-Milanovic J, Miloradovic Z, Ivanov M, Jovovic D, Vajic UJ, Zivotic M, Markovic-Lipkovski J, Mihailovic-Stanojevic N: Effects of single and combined losartan and tempol treatments on oxidative stress, kidney structure and function in spontaneously hypertensive rats with early course of proteinuric nephropathy. PLoS One 2016, 11:e0161706.10.1371/journal.pone.0161706Search in Google Scholar

24. Green LC, Wagner DA, Glogowski J, Skipper PL, Wishnok JS, Tannenbaum SR: Analysis of nitrate, nitrite, and [15N]nitrate in biological fluids. Anal Biochem 1982, 126:131-8.10.1016/0003-2697(82)90118-XSearch in Google Scholar

25. Nakayama T, Sato W, Kosugi T, Zhang L, Campbell-Thompson M, Yoshimura A, Croker BP, Richard J, Johnson RJ, Nakagawa T: Endothelial injury due to eNOS deficiency accelerates the progression of chronic renal disease in the mouse. Am J Physiol Renal Physiol 2009, 296:F317-F327.10.1152/ajprenal.90450.2008406350819036847Search in Google Scholar

26. Takahashi T, Harris RC: Role of endothelial nitric oxide synthase in diabetic nephropathy: lessons from diabetic eNOS knockout mice. J. Diabetes Res. 2014, 2014:17 pages.10.1155/2014/590541421124925371905Search in Google Scholar

27. Szabo AJ, Wagner L, Erdely A, Lau K, Baylis C: Renal neuronal nitric oxide synthase protein expression as a marker of renal injury. Kidney Int. 2003, 64:1765-1771.10.1046/j.1523-1755.2003.00260.x14531809Search in Google Scholar

28. Smith C, Merchant M, Fekete A, Nyugen HL, Oh P, Tain YL, Jon B, Klein JB, Baylis C: Splice variants of neuronal nitric oxide synthase are present in the rat kidney. Nephrol Dial Transplant 2009, 24:1422-1428.10.1093/ndt/gfn676272146119073653Search in Google Scholar

29. Zou J, Yaoita E, Watanabe Y, Yoshida Y, Nameta M, Li H, Qu Z., Yamamoto T: Upregulation of nestin, vimentin, and desmin in rat podocytes in response to injury. Virchows. Arch. 2006, 448:485-492.10.1007/s00428-005-0134-916418842Search in Google Scholar

30. Van Beneden K, Van Grunsven LA, Geers C, Pauwels M, Desmouliere A, Verbeelen D, Geerts A, Van den Branden C: CRBP-I in the renal tubulointerstitial compartment of healthy rats and rats with renal fibrosis. Nephrol Dial Transplant 2008, 23:3464-71.10.1093/ndt/gfn29018503097Search in Google Scholar

31. Young BA, Burdmann EA, Johnson RJ, Alpers CE, Giachelli CM, Eng E, Andoh T, Bennett W, Couse WG: Cellular proliferation and macrophage influx precede interstitial fibrosis in cyclosporine nephrotoxicity. Kidney Int 1995, 48:439-448.10.1038/ki.1995.3127564111Search in Google Scholar

32. Carlos CP, Sonehara NM, Oliani SM, Burdmann EA: Predictive Usefulness of Urinary Biomarkers for the Identification of Cyclosporine A-Induced Nephrotoxicity in a Rat Model. PLoS ONE 2014, 9: e103660.10.1371/journal.pone.0103660411497925072153Search in Google Scholar

33. Bravo J, Quiroz Y, Pons H, Parra G, Herrera-Acosta J, Johnson RJ, Rodriguez-Iturbe B: Vimentin and heat shock protein expression are induced in the kidney by angiotensin and by nitric oxide inhibition. Kidney Int. 2003, 64:546-551.10.1046/j.1523-1755.64.s86.9.x12969127Search in Google Scholar

34. Ji Z, Huang C, Liang C, Chen B, Chen S, Sun W: Protective effects of blocking reninangiotensin system on the progression of renal injury in glomerulosclerosis. Cell. Mol. Immunol. 2005, 2:150-154.Search in Google Scholar

35. Ozen S, Usta Y, Sahin-Erdemli I, Orhan D, Gumusel B, Yang B, Gursoy Y, Tulunay O, Dalkara T, Bakkaloglu A, El-Nahas M: Association of nitric oxide production and apoptosis in a model of experimental nephropathy. Nephrol Dial Transplant 2001, 16:32-38.10.1093/ndt/16.1.3211208990Search in Google Scholar

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