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Vol. 23, No. 1, 2003
Issue release date: January–February 2003 (October 2002)
Am J Nephrol 2003;23:2–7
(DOI:10.1159/000066303)

Hyperuricemia Causes Glomerular Hypertrophy in the Rat

Nakagawa T.a · Mazzali M.a · Kang D.-H.a · Kanellis J.a · Watanabe S.a · Sanchez-Lozada L.G.b · Rodriguez-Iturbe B.c · Herrera-Acosta J.b · Johnson R.J.a
aDepartmentof Medicine-Nephrology, Baylor College of Medicine, Houston, Tex., USA; bNephrology, Instituto Nacional de Cardiología I, Mexico City, Mexico; cHospital Universitario and Universidad del Zulia, Maracaibo, Venezuela
email Corresponding Author

Abstract

Background/Aims: Rats with mild hyperuricemia develop systemic hypertension, interstitial renal disease, afferent arteriolopathy, and increased renin expression [Mazzali et al.: Am J Physiol 2002;6:F991–F997]. We hypothesized that hyperuricemia might also induce glomerular changes. Methods: We reviewed renal biopsies of rats previously made hyperuricemic for 7 weeks with the uricase inhibitor, oxonic acid. Controls included normal rats and oxonic acid-treated rats administered allopurinol, benziodarone, hydrochlorothiazide, or enalapril. Glomeruli were examined for size (computer image analysis) and structure (histology). An additional group of rats were administered oxonic acid or control diet for 6 months. Results: Renal biopsies showed that hyperuricemic rats had a 30% increase in glomerular tuft area (p < 0.01); these changes were prevented by allopurinol and benziodarone. Control of blood pressure with hydrochlorothiazide did not prevent the development of glomerular hypertrophy, whereas enalapril partially reduced the glomerular hypertrophy. Prolonged hyperuricemia was associated with the development of microalbuminuria (p < 0.05) and glomerulosclerosis (22 vs. 10%, p < 0.05) compared to control rats. Conclusions: Hyperuricemic rats develop glomerular hypertrophy that can be prevented in part by ACE inhibitor therapy. Prolonged hyperuricemia is associated with the development of glomerulosclerosis in the rat.


 goto top of outline Key Words

  • Uric acid
  • Glomerular hypertrophy
  • Glomerulosclerosis

 goto top of outline Abstract

Background/Aims: Rats with mild hyperuricemia develop systemic hypertension, interstitial renal disease, afferent arteriolopathy, and increased renin expression [Mazzali et al.: Am J Physiol 2002;6:F991–F997]. We hypothesized that hyperuricemia might also induce glomerular changes. Methods: We reviewed renal biopsies of rats previously made hyperuricemic for 7 weeks with the uricase inhibitor, oxonic acid. Controls included normal rats and oxonic acid-treated rats administered allopurinol, benziodarone, hydrochlorothiazide, or enalapril. Glomeruli were examined for size (computer image analysis) and structure (histology). An additional group of rats were administered oxonic acid or control diet for 6 months. Results: Renal biopsies showed that hyperuricemic rats had a 30% increase in glomerular tuft area (p < 0.01); these changes were prevented by allopurinol and benziodarone. Control of blood pressure with hydrochlorothiazide did not prevent the development of glomerular hypertrophy, whereas enalapril partially reduced the glomerular hypertrophy. Prolonged hyperuricemia was associated with the development of microalbuminuria (p < 0.05) and glomerulosclerosis (22 vs. 10%, p < 0.05) compared to control rats. Conclusions: Hyperuricemic rats develop glomerular hypertrophy that can be prevented in part by ACE inhibitor therapy. Prolonged hyperuricemia is associated with the development of glomerulosclerosis in the rat.

Copyright © 2003 S. Karger AG, Basel


 goto top of outline References
  1. Johnson RJ, Kivlighn SD, Kim YG, Suga S, Fogo AB: Reappraisal of the pathogenesis and consequences of hyperuricemia in hypertension, cardiovascular disease and renal disease. Am J Kidney Dis 1999;33:225–234.

    External Resources

  2. Yü T, Berger L: Impaired renal function in gout: Its association with hypertensive vascular disease and intrinsic renal disease. Am J Med 1982;72:95–100.

    External Resources

  3. Beck L: Requiem for gouty nephropathy. Kidney Int 1986;30:280–287.
  4. Nickeleit V, Mihatsch MJ: Uric acid nephropathy and end-stage renal disease: Review of a non-disease. Nephrol Dial Transplant 1997;12:1832–1838.
  5. Wu X, Muzny DM, Lee CC, Caskey CT: Two independent mutational events in the loss of urate oxidase during hominoid evolution. J Mol Evol 1992;34:78–84.

    External Resources

  6. Mazzali M, Hughes J, Kim YG, Jefferson J, Kang DH, Gordon KL, Lan HY, Kivlighn S, Johnson RJ: Elevated uric acid increases blood pressure in the rat by a novel crystal-independent mechanism. Hypertension 2001;35:1101–1106.
  7. Mazzali M, Kanellis J, Han L, Feng L, Chen Q, Kang DH, Watanabe S, Nakagawa T, Lan HY, Johnson RJ: Hyperuricemia induces a primary renal arteriolopathy in rats by a blood pressure-independent mechanism. Am J Physiol Renal Physiol 2002;6:F991–F997.
  8. Fogo AB: Glomerular hypertension, abnormal glomerular growth and progression of renal diseases. Kidney Int 2000;57:S15–S21.

    External Resources

  9. Bunag RD, Butterfield J: Tail-cuff blood pressure measurement without external preheating in awake rats. Hypertension 1982;4:898–903.

    External Resources

  10. Henry RJ, Sobel C, Kim J: A modified carbonate phosphotungstate method for the determination of uric acid and comparison with the spectrophotometric uricase method. Am J Clin Pathol 1957;28:152–160.
  11. Kang DH, Hughes J, Mazzali M, George FS, Johnson RJ: Impaired angiogenesis in the remnant kidney model. II. Vascular endothelial growth factor administration reduces renal fibrosis and stabilizes renal function. J Am Soc Nephrol 2001;12:1448–1457.
  12. Saito I, Saruta T, Kondo K, Nakamura R, Ogura T, Yamagami K, Ozawa Y, Kato E: Serum uric acid and the renin-angiotensin system in hypertension. J Am Geriatr Soc 1978;26:241–247.

    External Resources

  13. Newburger J, Combs AB, Hsu TF: Diurnal variation in serum uric acid of rats fed potassium oxonate. Drug Chem Toxicol 1978;1:231–235.

    External Resources

  14. Mazzali M, Kim YG, Suga S, Gordon KL, Kang DK, Jefferson JA, Hughes J, Kivlighn SD, Lan HY, Johnson RJ: Hyperuricemia exacerbates chronic cyclosporine nephropathy. Transplantation 2001;71:900–905.

    External Resources


 goto top of outline Author Contacts

Takahiko Nakagawa
Department of Medicine-Nephrology
One Baylor Plaza ALKEK N520
Houston, TX 77030 (USA)
Tel. +1 713 798 5835, Fax +1 713 798 5010, E-Mail takahiko@bcm.tmc.edu


 goto top of outline Article Information

Received: June 30, 2002
Accepted: July 24, 2002
Number of Print Pages : 6
Number of Figures : 5, Number of Tables : 1, Number of References : 14


 goto top of outline Publication Details

American Journal of Nephrology
Founded 1981 and edited until 2002 by S.G. Massry

Vol. 23, No. 1, Year 2003 (Cover Date: January-February 2003)

Journal Editor: G. Bakris, Chicago, Ill.
ISSN: 0250–8095 (print), 1421–9670 (Online)

For additional information: http://www.karger.com/ajn


Copyright / Drug Dosage / Disclaimer

Copyright: 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 or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
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 goverment 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.

Abstract

Background/Aims: Rats with mild hyperuricemia develop systemic hypertension, interstitial renal disease, afferent arteriolopathy, and increased renin expression [Mazzali et al.: Am J Physiol 2002;6:F991–F997]. We hypothesized that hyperuricemia might also induce glomerular changes. Methods: We reviewed renal biopsies of rats previously made hyperuricemic for 7 weeks with the uricase inhibitor, oxonic acid. Controls included normal rats and oxonic acid-treated rats administered allopurinol, benziodarone, hydrochlorothiazide, or enalapril. Glomeruli were examined for size (computer image analysis) and structure (histology). An additional group of rats were administered oxonic acid or control diet for 6 months. Results: Renal biopsies showed that hyperuricemic rats had a 30% increase in glomerular tuft area (p < 0.01); these changes were prevented by allopurinol and benziodarone. Control of blood pressure with hydrochlorothiazide did not prevent the development of glomerular hypertrophy, whereas enalapril partially reduced the glomerular hypertrophy. Prolonged hyperuricemia was associated with the development of microalbuminuria (p < 0.05) and glomerulosclerosis (22 vs. 10%, p < 0.05) compared to control rats. Conclusions: Hyperuricemic rats develop glomerular hypertrophy that can be prevented in part by ACE inhibitor therapy. Prolonged hyperuricemia is associated with the development of glomerulosclerosis in the rat.



 goto top of outline Author Contacts

Takahiko Nakagawa
Department of Medicine-Nephrology
One Baylor Plaza ALKEK N520
Houston, TX 77030 (USA)
Tel. +1 713 798 5835, Fax +1 713 798 5010, E-Mail takahiko@bcm.tmc.edu


 goto top of outline Article Information

Received: June 30, 2002
Accepted: July 24, 2002
Number of Print Pages : 6
Number of Figures : 5, Number of Tables : 1, Number of References : 14


 goto top of outline Publication Details

American Journal of Nephrology
Founded 1981 and edited until 2002 by S.G. Massry

Vol. 23, No. 1, Year 2003 (Cover Date: January-February 2003)

Journal Editor: G. Bakris, Chicago, Ill.
ISSN: 0250–8095 (print), 1421–9670 (Online)

For additional information: http://www.karger.com/ajn


Copyright / Drug Dosage

Copyright: 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 or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
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 goverment 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.

References

  1. Johnson RJ, Kivlighn SD, Kim YG, Suga S, Fogo AB: Reappraisal of the pathogenesis and consequences of hyperuricemia in hypertension, cardiovascular disease and renal disease. Am J Kidney Dis 1999;33:225–234.

    External Resources

  2. Yü T, Berger L: Impaired renal function in gout: Its association with hypertensive vascular disease and intrinsic renal disease. Am J Med 1982;72:95–100.

    External Resources

  3. Beck L: Requiem for gouty nephropathy. Kidney Int 1986;30:280–287.
  4. Nickeleit V, Mihatsch MJ: Uric acid nephropathy and end-stage renal disease: Review of a non-disease. Nephrol Dial Transplant 1997;12:1832–1838.
  5. Wu X, Muzny DM, Lee CC, Caskey CT: Two independent mutational events in the loss of urate oxidase during hominoid evolution. J Mol Evol 1992;34:78–84.

    External Resources

  6. Mazzali M, Hughes J, Kim YG, Jefferson J, Kang DH, Gordon KL, Lan HY, Kivlighn S, Johnson RJ: Elevated uric acid increases blood pressure in the rat by a novel crystal-independent mechanism. Hypertension 2001;35:1101–1106.
  7. Mazzali M, Kanellis J, Han L, Feng L, Chen Q, Kang DH, Watanabe S, Nakagawa T, Lan HY, Johnson RJ: Hyperuricemia induces a primary renal arteriolopathy in rats by a blood pressure-independent mechanism. Am J Physiol Renal Physiol 2002;6:F991–F997.
  8. Fogo AB: Glomerular hypertension, abnormal glomerular growth and progression of renal diseases. Kidney Int 2000;57:S15–S21.

    External Resources

  9. Bunag RD, Butterfield J: Tail-cuff blood pressure measurement without external preheating in awake rats. Hypertension 1982;4:898–903.

    External Resources

  10. Henry RJ, Sobel C, Kim J: A modified carbonate phosphotungstate method for the determination of uric acid and comparison with the spectrophotometric uricase method. Am J Clin Pathol 1957;28:152–160.
  11. Kang DH, Hughes J, Mazzali M, George FS, Johnson RJ: Impaired angiogenesis in the remnant kidney model. II. Vascular endothelial growth factor administration reduces renal fibrosis and stabilizes renal function. J Am Soc Nephrol 2001;12:1448–1457.
  12. Saito I, Saruta T, Kondo K, Nakamura R, Ogura T, Yamagami K, Ozawa Y, Kato E: Serum uric acid and the renin-angiotensin system in hypertension. J Am Geriatr Soc 1978;26:241–247.

    External Resources

  13. Newburger J, Combs AB, Hsu TF: Diurnal variation in serum uric acid of rats fed potassium oxonate. Drug Chem Toxicol 1978;1:231–235.

    External Resources

  14. Mazzali M, Kim YG, Suga S, Gordon KL, Kang DK, Jefferson JA, Hughes J, Kivlighn SD, Lan HY, Johnson RJ: Hyperuricemia exacerbates chronic cyclosporine nephropathy. Transplantation 2001;71:900–905.

    External Resources