Original Report: Laboratory Investigation
Role of Angiotensin II on Dihydrofolate Reductase, GTP-Cyclohydrolase 1 and Nitric Oxide Synthase Expressions in Renal Ischemia-ReperfusionSeujange Y.a · Eiam-Ong S.b · Tirawatnapong T.c · Eiam-Ong S.d
aInter-department of Physiology, Graduate School, and Departments of bPhysiology, cMicrobiology and dMedicine, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
Do you have an account?
- Rent for 48h to view
- Buy Cloud Access for unlimited viewing via different devices
- Synchronizing in the ReadCube Cloud
- Printing and saving restrictions apply
Rental: USD 8.50
Cloud: USD 20.00
Article / Publication Details
Background: The present study was conducted to investigate the role of renal ischemia-reperfusion (IR) and angiotensin II (ANG II) on mRNA and protein levels of renal dihydrofolate reductase (DHFR), GTP-cyclohydrolase 1 (GTP- CH 1), and endothelial and inducible nitric oxide synthase (eNOS and iNOS, respectively). Methods: Male Wistar rats were sham operated or received IR (30 min occlusion, and reperfusion for 1 day). Each group was treated separately with water, angiotensin-converting enzyme inhibitor (ACEI) and ANG II receptor type 1 blocker (ARB) for 1 day before the sham operation or IR, and continuously for 1 day after the operation. The mRNA and protein levels were detected by RT-PCR and Western blot, respectively. Results: IR decreased DHFR mRNA and protein levels (p < 0.01), both of which were restored by ACEI or ARB, whereas GTP-CH 1 expression was unaltered. IR suppressed eNOS dimer while enhancing the monomer (p < 0.01). IR augmented iNOS mRNA, total iNOS protein and iNOS monomer (all p < 0.01) which were attenuated by ACEI or ARB. Conclusion: Our study is the first to demonstrate that the heightened ANG II in IR, via stimulation of ANG II receptor type 1, suppresses DHFR and eNOS dimer, while activating both iNOS mRNA and protein levels.
© 2008 S. Karger AG, Basel
- Alderton WK, Cooper CE, Knowles RG: Nitric oxide syntheses: structure, function and inhibition. Biochem J 2001;357:593–615.
- Thony B, Auerbach G, Blau N: Tetrahydrobiopterin biosynthesis, regeneration and functions. Biochem J 2000;347:1–16.
- Channon KM: Tetrahydrobiopterin: regulator of endothelial nitric oxide synthase in vascular disease. Trends Cardiovasc Med 2004;14:323–327.
- Chalupsky K, Cai H: Endothelial dihydrofolate reductase: critical for nitric oxide bioavailability and role in angiotensin II uncoupling of endothelial nitric oxide synthase. Proc Natl Acad Sci USA 2005;102:9056–9061.
- Shimizu S, Shiota K, Yamamoto SK, Miyasaka Y, Ishii M, Watabe T: Hydrogen peroxide stimulates tetrahydrobiopterin synthesis through the induction of GTP-cyclohydrolase 1 and increases nitric oxide synthase activity in vascular endothelial cells. Free Radic Biol Med 2003;34:1343–1352.
Allred AJ, Chappell MC, Ferrario CM, Diz D: Differential actions of renal ischemic injury on the intrarenal angiotensin system. Am J Physiol 2000;279:F636–F645.
- Kontogiannis J, Burns K: Role of AT1 angiotensin II receptors in renal ischemic injury. Am J Physiol 1998;274:F79–F90.
- Vargas AV, Robinson AV, Schulak JA: Captopril amelioration of renal reperfusion injury. J Surg Res1994;57:28–32.
- Barrilli A, Molinas S, Petrini G, Menacho M, Elias MM: Losartan reverses fibrotic changes in cortical renal tissue induced by ischemia or ischemia-reperfusion without changes in renal function. Mol Cell Biochem 2004;260:161–170.
Seujange Y, Kittikowit W, Eiam-Ong S, Eiam-Ong S: Lipid peroxidation and renal injury in renal ischemic reperfusion: effect of angiotensin inhibition. J Med Assoc Thai 2006;89:1686–1693.
- Rhoden EL, Rhoden CR, Lucas ML, Pereira-Lima L, Zettler C, Bello-Klein A: The role of nitric oxide pathway in the renal ischemia-reperfusion injury in rats. Transpl Immunol2002;10:277–284.
Kakoki M, Hirata Y, Hayakawa H, Suzuki E, Nagata D, Jojo A: Effect of tetrahydrobiopterin on endothelial dysfunction in rats with ischemic acute renal failure.J Am Soc Nephrol 2000;11:301–309.
- Manucha W, Oliveros L, Carrizo L, Seltzer A, Valles P: Losartan modulates on NOS isoforms and COX-2 expression in early renal fibrogenesis in unilateral obstruction. Kidney Int 2004;65:2091–2107.
- Paller MS, Hoidal JR, Ferris TF: Oxygen free radicals in ischemic acute renal failure. J Clin Invest1984;74:1156–1164.
- Linas SL, Whittenburg D, Repine JE: Role of xanthine oxidase in ischemia-reperfusion injury. Am J Physiol 1990;258:F711–F716.
- Vinas JL, Sola A, Genesca M, Alfaro N, Pi F, Hotter G: NO and NOS isoforms in the development of apotosis in renal ischemia/reperfusion. Free Radic Biol Med 2006;40:992–1003.
- Ishimura T, Fujisawa M, Isotani S, Iijima K, Yoshikawa N, Kamidono S: Endothelial nitric oxide synthase expression in ischemia-reperfusion injury after living related-donor renal transplantation. Transpl Int2002;15:635–640.
- Schramm L, La M, Heidbreder E, Hecker M, Beckman J, Lopau K, Zimmermann J, Rendl J, Reiners C, Winderl S, Wanner C, Schmidt H: L-arginine deficiency and supplementation in experimental acute renal failure and in human kidney transplantation. Kidney Int 2002;61:1423–1432.
- Mitterbauer C, Schwarz C, Hauser P, Steininger R, Regele HM, Rosenkranz A, Oberbauer R: Impaired tubulointerstitial expression of endothelin-1 and nitric oxide isoforms in donor kidney biopsies with postischemic acute renal failure. Transplantation 2003;76:715–720.
- Rodriguez-Crespo I, Gerber Counts N, Ortiz de Montellanos P: Endothelial nitric oxide synthase. J Biol Chem 1996;271:11462–11467.
- Tzeng E, Billiar T, Robbins P, Loftus M, Stuehr D: Expression of human inducible nitric oxide synthase in a tetrahydrobiopterin (BH4)-deficient cell line: BH4 promotes assembly of enzyme subunits into an active dimer. Proc Natl Acad Sci USA 1995;92:11771–11775.
- Noiri E, Peresleni T, Miller F, Goligorsky MS: In vivo targeting of inducible NO synthase with oligodeoxynucleotides protects rat kidney against ischemia. J Clin Invest 1996;97:2377–2383.
- Chiao H, Kohda Y, McLeroy P, Craig L, Housini I, Star RA: Alpha-melanocyte-stimutating hormone protects against renal injury after ischemia in mice and rats. J Clin Invest1997;99:1165–1172.
- Araki M, Fahmy N, Zhou L, Kumon H, Krishnamurthi V, Goldfarb D: Expression of IL-8 during reperfusion of renal allografts is dependent on ischemic time. Transplantation 2006;81:783–788.
- Donnahoo KK, Shames BD, Harken AH, Meldrum DR: Review article: the role of tumor necrosis factor in renal ischemia-reperfusion injury. J Urol 1999;162:196–203.
- Furuichi K, Wada T, Iwata Y, Kokubo S, Hara A, Yamahana J, Sugaya T, Iwakura Y, Matsushima K, Asano M, Yokoyama H, Kaneko S: Interleukin-1-dependent sequential chemokine expression and inflammatory cell infiltration in ischemia-reperfusion injury. Crit Care Med2006;34:2447–2455.
Ruiz-Ortega M, Ruperez M, Lorenzo O, Esteban V, Blanco J, Mezzano S, Egido J: Angiotensin II regulates the synthesis of proinflammatory cytokines and chemokines in the kidney. Kidney Int2002;82(suppl):12–22.
- Abu-Soud HM, Wang J, Rousseau DL, Fukuto JM, Ignarro LJ, Stuehr DJ: Neuronal nitric oxide synthase self-inactivates by forming a ferrous-nitrosyl complex during aerobic catalysis. J Biol Chem 1995;270:22997–23006.
Abu-Soud HM, Ichimori K, Nakazawa H, Stuehr DJ: Regulation of inducible nitric oxide synthase by self-generated NO.Biochemistry 2001;40:6876–6881.
- Chen Y, Panda K, Stuehr DJ: Control of nitric oxide synthase dimer assembly by a heme-NO-dependent mechanism. Biochemistry 2002;41:4618–4625.
- Li D, Hayden EY, Panda K, Stuehr DJ, Deng H, Rousseau DL: Regulation of the monomer-dimer equilibrium in inducible nitric-oxide synthase by nitric oxide. J Biol Chem 2006;281:8197–8204.
- Albakri QA, Stuehr DJ: Intracellular assembly of inducible NO synthase is limited by nitric oxide-mediated changes in heme insertion and availability. J Biol Chem 1996;271:5414–5421.
Article / Publication Details
Copyright / Drug Dosage / DisclaimerCopyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.