Published online before print February 7, 2008, doi: 10.1161/HYPERTENSIONAHA.107.101345
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
(Hypertension. 2008;51:1000.)
© 2008 American Heart Association, Inc.
Go Red Editorial Commentaries |
Sex and the Kidney
From the Department of Physiology and Biophysics and Center for Excellence in Cardiovascular-Renal Research, University of Mississippi Medical Center, Jackson.
Correspondence to Jane F. Reckelhoff, Department of Physiology and Biophysics, University of Mississippi Medical Center, 2500 North State St, Jackson, MS 39216-4505. E-mail jreckelhoff{at}physiology.umsmed.edu
Several lines of evidence indicate that there are sex differences in the incidence and severity of cardiovascular and renal disease. Men are more prone to develop chronic kidney disease (CKD) and to progresses to end-stage renal disease than are women, when all-cause incidence rates are considered.1 When a primary diagnosis is taken into account, this assertion holds true for many causes of CKD, such as IgA or membranous nephropathy, hypertensive nephropathy, or polycystic kidney disease.2 However, in the case of diabetic renal disease, the sexual dimorphism favoring women is not as clear cut, and clinical data are conflicting.2
Extensive experimental studies document a role for sex hormones, androgens and estrogens, in the regulation of cardiovascular and renal physiology and pathology. Generally, beneficial effects of estrogens were considered to underlie the relative protection of women against cardiovascular disease and to explain the loss of such protection after menopause. However, recent data from the Women’s Health Initiative study disproved the expected beneficial results of female sex hormone replacement on primary events associated with cardiovascular disease. The alternative explanation, that the presence of androgens and not the absence of estrogens predisposes men to developing cardiovascular disease and CKD, has recently received increasing attention from basic and clinical investigators, but preconceived notions and entrenched dogma in this field have been difficult to overcome.3
Androgens have been demonstrated to affect multiple hormonal and autacoid systems, which participate in the regulation of blood pressure and renal function. Testosterone stimulates various key components of the systemic and renal renin-angiotensin system and the endothelin system and promotes oxidative stress,4–7 which ultimately may exacerbate the progression of renal disease. In light of these findings, the fact that androgen levels actually decrease in men suffering from chronic disease, such as hypertension, diabetes, and CKD, is puzzling. Clinicians currently interpret these data to mean that lower testosterone levels may be the cause of cardiovascular and renal ailments and prescribe androgen supplements to these patients, with the added benefit of improved libido and well being. No large-scale clinical studies are available, however, to support this hypothesis and to ensure that testosterone supplementation would not exacerbate the progression of renal disease, as experimental studies suggest.8
Men with diabetes have levels of testosterone that are below the norm of the general population, and uncontrolled diabetes is associated with defective reproductive capacity.9 Diabetes is the major cause of CKD and progression to end-stage renal disease. In the study published in this issue of Hypertension, Xu et al10 took steps toward understanding the effect of sex hormones on the development of diabetic renal disease in the experimental model of streptozotocin-induced type 1 diabetes in male rats. They removed testosterone by castration and followed the development of renal injury after the induction of diabetes, while monitoring circulating levels of sex hormones. They found that castrated rats fared worse that intact male rats and developed more albuminuria, glomerulosclerosis, tubulointerstitial fibrosis, and deposition of collagen and had higher renal expression of transforming growth factor-β and macrophage infiltration. These data alone may suggest that removal of androgens exacerbates diabetic renal disease. However, the authors’ examination of not only testosterone but also estradiol and progesterone levels in their experiment reveal a far more complex picture. Diabetic rats had lower testosterone levels as compared with intact, nondiabetic animals, such as found in men, with diabetes. This may be because of defective basal and pulsatile luteinizing hormone secretion and insufficient testosterone secretion in diabetes and may involve dysregulation of the KiSS-1/GPR54 pathway in the hypothalamus.11 In contrast, circulating levels of estradiol were actually increased 2.9-fold by diabetes in male rats and were not altered by castration. This finding calls into question the role of the absolute decrease in testosterone levels as the mechanism for the accelerated renal injury seen with castration in the present study. One possible alternative explanation would be that the increase in estradiol in diabetic males is the culprit. Previous studies from the same laboratory showing that replacement of estradiol in female rats improves renal function and structure in diabetic nephropathy12 may point to the importance of heterologous sex hormone effects. Indeed, a clinical study of estrogen administration to men after myocardial infarction was interrupted in the 1970s because of increased deaths and incidence of reinfarction.13 Whether the increase in estradiol alone or rather the decrease in the ratio of testosterone/estradiol in male diabetic rats is responsible for the progression of diabetic renal disease, as suggested by correlation analysis in the study by Xu et al,10 remains to be established.
Another obvious question to be addressed is whether supplementation with testosterone in diabetic males may alter the course of diabetic nephropathy. This is especially important in light of the current trend of prescription androgen supplementation in men with CKD, where actual levels of sex hormones achieved with therapy are rarely monitored. Also, the source of increased circulating estradiol when the substrate for its synthesis (testosterone) is decreased, by diabetes and/or castration, is still elusive and deserves further investigation.
Studies from several laboratories indicate that the presence of testosterone plays a permissive role in the development of hypertensive renal disease and also ischemia-reperfusion–induced renal failure. Despite the chronic decline in testosterone levels in these settings, complete removal of testosterone by castration may prevent further activation of the renin-angiotensin system, oxidative stress, and inflammatory processes6,8,14 and protect against renal injury. The fact that castration accelerates diabetic nephropathy10 may relate to different pathogenic mechanisms involved. A major initiating event in diabetic nephropathy is glomerular hyperperfusion and hyperfiltration, and male diabetic rats may be exposed to excessive vasodilator effects of increased circulating estradiol on the preglomerular vasculature. In addition, removal of the anabolic effects of testosterone in the setting of the wasting syndrome of uncontrolled diabetes may contribute to further deterioration of renal function. Also, expression of profibrotic molecules, such as transforming growth factor-β and matrix degradation enzymes, may be differentially controlled by sex hormones,15 which may explain the effect of castration on these parameters as found by Xu et al.10
In summary, one thing is certain: sex matters. The study of Xu et al,10 far from exhausting the possible explanations, opens new avenues for research into the role of sex hormones in altering the course of diabetic nephropathy. As conventional paradigms fail to encompass the wealth of contemporary experimental evidence, clinical practice would certainly benefit from a thorough understanding of the mechanisms underlying the effects of sex hormones on the kidney and cardiovascular system.
 |
Acknowledgments |
|---|
Sources of Funding
This work was supported by a postdoctoral fellowship award from the Southeast Affiliate of the American Heart Association (0525320B to R.I.) and National Institutes of Health grants HL51971, HL66072, and HL69194. R.I. has also received a postdoctoral fellowship award of >$10 000 from the American Heart Association. J.F.R. has received 2 ROI and 1 POI awards of >$10 000.
Disclosures
None.
|
Footnotes |
|---|
The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.
This paper was sent to Ernesto L. Schiffrin, consulting editor, for review by expert referees, editorial decision, and final disposition.
|
References |
|---|
 Top References |
|---|
- US Renal Data System. USRDS 2007 Annual Data Report: Atlas of End-Stage Renal Disease in the United States. Bethesda, MD: National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases; 2007.
- Neugarten J, Acharya A, Silbiger SR. Effect of gender on the progression of nondiabetic renal disease: a meta-analysis. J Am Soc Nephrol. 2000; 11: 319–329.
[Abstract/Free Full Text] - Reckelhoff JF. Sex steroids, cardiovascular disease, and hypertension: unanswered questions and some speculations. Hypertension. 2005; 45: 170–174.
[Free Full Text] - Baltatu O, Cayla C, Iliescu R, Andreev D, Jordan C, Bader M. Abolition of hypertension-induced end-organ damage by androgen receptor blockade in transgenic rats harboring the mouse ren-2 gene. J Am Soc Nephrol. 2002; 13: 2681–2687.
[Abstract/Free Full Text] - Reckelhoff JF, Zhang H, Srivastava K. Gender differences in development of hypertension in spontaneously hypertensive rats: role of the renin-angiotensin system. Hypertension. 2000; 35: 480–483.
[Abstract/Free Full Text] - Iliescu R, Cucchiarelli VE, Yanes LL, Iles JW, Reckelhoff JF. Impact of androgen-induced oxidative stress on hypertension in male SHR. Am J Physiol Regul Integr Comp Physiol. 2007; 292: R731–R735.
[Abstract/Free Full Text] - Yanes LL, Romero DG, Cucchiarelli VE, Fortepiani LA, Gomez-Sanchez CE, Santacruz F, Reckelhoff JF. Role of endothelin in mediating postmenopausal hypertension in a rat model. Am J Physiol Regul Integr Comp Physiol. 2005; 288: R229–R233.
[Abstract/Free Full Text] - Reckelhoff JF, Yanes LL, Iliescu R, Fortepiani LA, Granger JP. Testosterone supplementation in aging men and women: possible impact on cardiovascular-renal disease. Am J Physiol Renal Physiol. 2005; 289: F941–F948.
[Abstract/Free Full Text] - Rhoden EL, Ribeiro EP, Teloken C, Souto CA. Diabetes mellitus is associated with subnormal serum levels of free testosterone in men. BJU Int. 2005; 96: 867–870.[CrossRef][Medline] [Order article via Infotrieve]
- Xu Q, Wells CC, Garman JH, Asico L, Escano CS, Maric C. Imbalance in sex hormone levels exacerbates diabetic renal disease. Hypertension. 2008; 51: 1218–1224.
[Abstract/Free Full Text] - Castellano JM, Navarro VM, Fernandez-Fernandez R, Roa J, Vigo E, Pineda R, Dieguez C, Aguilar E, Pinilla L, Tena-Sempere M. Expression of hypothalamic KiSS-1 system and rescue of defective gonadotropic responses by kisspeptin in streptozotocin-induced diabetic male rats. Diabetes. 2006; 55: 2602–2610.[CrossRef][Medline] [Order article via Infotrieve]
- Mankhey RW, Bhatti F, Maric C. 17β-Estradiol replacement improves renal function and pathology associated with diabetic nephropathy. Am J Physiol Renal Physiol. 2005; 288: F399–F405.
[Abstract/Free Full Text] - The Coronary Drug Project. Findings leading to discontinuation of the 2.5-mg day estrogen group. The coronary Drug Project Research Group. JAMA. 1973; 226: 652–657.[CrossRef][Medline] [Order article via Infotrieve]
- Fortepiani LA, Yanes L, Zhang H, Racusen LC, Reckelhoff JF. Role of androgens in mediating renal injury in aging SHR. Hypertension. 2003; 42: 952–955.
[Abstract/Free Full Text] - Natoli AK, Medley TL, Ahimastos AA, Drew BG, Thearle DJ, Dilley RJ, Kingwell BA. Sex steroids modulate human aortic smooth muscle cell matrix protein deposition and matrix metalloproteinase expression. Hypertension. 2005; 46: 1129–1134.
[Abstract/Free Full Text]
Related Article:
- Imbalance in Sex Hormone Levels Exacerbates Diabetic Renal Disease
- Qin Xu, Corinne C. Wells, Joseph H. Garman, Laureano Asico, Crisanto S. Escano, and Christine Maric
Hypertension 2008 51: 1218-1224.[Abstract] [Full Text] [PDF]
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||