HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 279, Issue 50, 52282-52292, December 10, 2004

This Article Full Text Full Text (PDF) All Versions of this Article: 279/50/52282    most recent M407629200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Park, K. M. Articles by Bonventre, J. V. Search for Related Content PubMed PubMed Citation Articles by Park, K. M. Articles by Bonventre, J. V. Social Bookmarking                      What's this?

Testosterone Is Responsible for Enhanced Susceptibility of Males to Ischemic Renal Injury^*

Kwon Moo Park, Jee In Kim, Youngkeun Ahn¶||, Andrew J. Bonventre, and Joseph V. Bonventre**

From the Renal Division, Brigham and Women's Hospital, Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115, the Department of Anatomy, School of Medicine, Kyungpook National University, Daegu, 700-422, Korea, the ^¶Cardiovascular Research Center, Massachusetts General Hospital, Charlestown, Massachusetts 02129, and the ^**Harvard-Massachusetts Institute of Technology Division of Health Sciences and Technology, Boston, Massachusetts 02115

Female mice are much more resistant to ischemia/reperfusion (I/R)-induced kidney injury when compared with males. Although estrogen administration can partially reduce kidney injury associated with I/R, we demonstrated that the presence of testosterone, more than the absence of estrogen, plays a critical role in gender differences in susceptibility of the kidney to ischemic injury. Testosterone administration to females increases kidney susceptibility to ischemia. Dihydrotestosterone, which can not be aromatized to estrogen, has effects equal to those of testosterone. Castration reduces the I/R-induced kidney injury. In contrast, ovariectomy does not affect kidney injury induced by ischemia in females. Testosterone reduces ischemia-induced activation of nitric oxide synthases (NOSs) and Akt and the ratio of extracellular signal related kinase (ERK) to c-jun N-terminal kinase (JNK) phosphorylation. Pharmacological (N-nitro-L-arginine) or genetic (endothelial NOS or inducible NOS) inhibition of NOSs in females enhances kidney susceptibility to ischemia. Nitric oxide increases Akt phosphorylation and protects Madin-Darby canine kidney epithelial cells from oxidant stress. Antagonists of androgen or estrogen receptors do not affect the gender differences. In conclusion, testosterone inhibits the post-ischemic activation of NOSs and Akt and the ratio of ERK to JNK phosphorylation through non-androgen receptor-medicated mechanisms, leading to increased inflammation and increased functional injury to the kidney. These findings provide a new paradigm for the design of therapies for ischemia/reperfusion injury and may be important to our understanding of the pathophysiology of acute renal failure in pregnancy where plasma androgen levels are elevated.

Received for publication, July 7, 2004 , and in revised form, September 3, 2004.

^* This work was supported by the Young Investigator Grant of the National Kidney Foundation, the Korea Research Foundation KRF-2004-003-E00245, and Kyungpook National University Research Fund 2004 (to K. M. P.) and by Grants DK 39773, DK 38452, DK46267, and NS 10828 from the National Institutes of Health (to J. V. B.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^|| Present address: Dept. of Cardiology, School of Medicine, Chonnam National University, Kwangju, 501–190, Korea.

To whom correspondence should be addressed: Harvard Institutes of Medicine, 4 Blackfan Circle, Boston, MA 02115. Tel.: 617-525-5960; Fax: 617-525-5965; E-mail: joseph_bonventre{at}hms.harvard.edu.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				D. I. Spratt, R. S. Kramer, J. R. Morton, F. L. Lucas, K. Becker, and C. Longcope Characterization of a prospective human model for study of the reproductive hormone responses to major illness Am J Physiol Endocrinol Metab, July 1, 2008; 295(1): E63 - E69. [Abstract] [Full Text] [PDF]

				M. P. Hutchens, J. Dunlap, P. D. Hurn, and P. O. Jarnberg Renal Ischemia: Does Sex Matter? Anesth. Analg., July 1, 2008; 107(1): 239 - 249. [Abstract] [Full Text] [PDF]

				T. Matsuzaki, T. Morisaki, W. Sugimoto, K. Yokoo, D. Sato, H. Nonoguchi, K. Tomita, T. Terada, K.-i. Inui, A. Hamada, et al. Altered Pharmacokinetics of Cationic Drugs Caused by Down-Regulation of Renal Rat Organic Cation Transporter 2 (Slc22a2) and Rat Multidrug and Toxin Extrusion 1 (Slc47a1) in Ischemia/Reperfusion-Induced Acute Kidney Injury Drug Metab. Dispos., April 1, 2008; 36(4): 649 - 654. [Abstract] [Full Text] [PDF]

				P. D. Metcalfe, J. A. Leslie, M. T. Campbell, D. R. Meldrum, K. L. Hile, and K. K. Meldrum Testosterone exacerbates obstructive renal injury by stimulating TNF-{alpha} production and increasing proapoptotic and profibrotic signaling Am J Physiol Endocrinol Metab, February 1, 2008; 294(2): E435 - E443. [Abstract] [Full Text] [PDF]

				J. C. Sullivan, L. Semprun-Prieto, E. I. Boesen, D. M. Pollock, and J. S. Pollock Sex and sex hormones influence the development of albuminuria and renal macrophage infiltration in spontaneously hypertensive rats Am J Physiol Regulatory Integrative Comp Physiol, October 1, 2007; 293(4): R1573 - R1579. [Abstract] [Full Text] [PDF]

				S. B. Ahmed, N. D.L. Fisher, and N. K. Hollenberg Gender and the Renal Nitric Oxide Synthase System in Healthy Humans Clin. J. Am. Soc. Nephrol., September 1, 2007; 2(5): 926 - 931. [Abstract] [Full Text] [PDF]

				A.-M. Heegaard, A. Corsi, C. C. Danielsen, K. L. Nielsen, H. L. Jorgensen, M. Riminucci, M. F. Young, and P. Bianco Biglycan Deficiency Causes Spontaneous Aortic Dissection and Rupture in Mice Circulation, May 29, 2007; 115(21): 2731 - 2738. [Abstract] [Full Text] [PDF]

				D. Obal, K. Rascher, C. Favoccia, S. Dettwiler, and W. Schlack Post-conditioning by a short administration of desflurane reduced renal reperfusion injury after differing of ischaemia times in rats Br. J. Anaesth., December 1, 2006; 97(6): 783 - 791. [Abstract] [Full Text] [PDF]

				D. I. Spratt, J. R. Morton, R. S. Kramer, S. W. Mayo, C. Longcope, and C. P. H. Vary Increases in serum estrogen levels during major illness are caused by increased peripheral aromatization Am J Physiol Endocrinol Metab, September 1, 2006; 291(3): E631 - E638. [Abstract] [Full Text] [PDF]

				J. Kim, I. S. Kil, Y. M. Seok, E. S. Yang, D. K. Kim, D. G. Lim, J.-W. Park, J. V. Bonventre, and K. M. Park Orchiectomy Attenuates Post-ischemic Oxidative Stress and Ischemia/Reperfusion Injury in Mice: A ROLE FOR MANGANESE SUPEROXIDE DISMUTASE J. Biol. Chem., July 21, 2006; 281(29): 20349 - 20356. [Abstract] [Full Text] [PDF]

				J. W. Card, M. A. Carey, J. A. Bradbury, L. M. DeGraff, D. L. Morgan, M. P. Moorman, G. P. Flake, and D. C. Zeldin Gender Differences in Murine Airway Responsiveness and Lipopolysaccharide-Induced Inflammation J. Immunol., July 1, 2006; 177(1): 621 - 630. [Abstract] [Full Text] [PDF]