Dose-dependent effects of dihydrotestosterone in the streptozotocin-induced diabetic rat kidney

Xu, Qin; Prabhu, Anjali; Xu, Shujing; Manigrasso, Michaele B.; Maric, Christine

doi:10.1152/ajprenal.00135.2009

Cited by 34 publications

(31 citation statements)

References 29 publications

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“…In addition, castration prevents the increase in RVR found in aged male SHR (46). However, Xu et al (47) demonstrated that low doses of DHT attenuated the development of albuminuria in streptozotocin-induced diabetic rats, indicating that the levels of plasma testosterone may play a crucial role in the progression of renal disease.…”

Section: Changes In Glomerular Filtration Ratementioning

confidence: 98%

Gender-dependent effects of aging on the kidney

Gava

Freitas

Meyrelles

et al. 2011

Braz J Med Biol Res

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Section: Changes In Glomerular Filtration Ratementioning

confidence: 98%

Gender-dependent effects of aging on the kidney

Gava

Freitas

Meyrelles

et al. 2011

Braz J Med Biol Res

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“…The level of testosterone produced by the supplements was not measured by Park et al (21), but it was likely high prior to the renal I/R maneuver. The dose of testosterone may be important since Xu et al (36) reported that circulating testosterone levels are also reduced in a rat model of streptozotocin diabetes and that supplemental high doses of androgens promote renal injury, but low doses, more physiological doses, protect against renal injury (36).…”

Section: N T-s H a M I N T-i /R -A K I C A S T-i /R -A K I C A S T-mentioning

confidence: 99%

Protective role of testosterone in ischemia-reperfusion-induced acute kidney injury

Soljancic

Ruiz

Chandrashekar

et al. 2013

American Journal of Physiology-Regulatory, Integrative and Comp

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-Men are at greater risk for renal injury and dysfunction after acute ischemia-reperfusion (I/R) than are women. Studies in animals suggest that the reason for the sex difference in renal injury and dysfunction after I/R is the protective effect of estrogens in females. However, a reduction in testosterone in men is thought to play an important role in mediating cardiovascular and renal disease, in general. In the present study, we tested the hypothesis that I/R of the kidney reduces serum testosterone, and that contributes to renal dysfunction and injury. Male rats that were subjected to renal ischemia of 40 min followed by reperfusion had a 90% reduction in serum testosterone by 3 h after reperfusion that remained at 24 h. Acute infusion of testosterone 3 h after reperfusion attenuated the increase in plasma creatinine and urinary kidney injury molecule-1 (KIM-1) at 24 h, prevented the reduction in outer medullary blood flow, and attenuated the increase in intrarenal TNF-␣ and the decrease in intrarenal VEGF at 48 h. Castration of males caused greater increases in plasma creatinine and KIM-1 at 24 h than in intact males with renal I/R, and treatment with anastrozole, an aromatase inhibitor, plus testosterone almost normalized plasma creatinine and KIM-1 in rats with renal I/R. These data show that renal I/R is associated with sustained reductions in testosterone, that testosterone repletion protects the kidney, whereas castration promotes renal dysfunction and injury, and that the testosterone-mediated protection is not conferred by conversion to estradiol. kidney injury molecule-1; sex; androgens; vascular endothelial growth factor ACUTE KIDNEY INJURY (AKI) is thought to affect ϳ2-5% of all hospitalized individuals in the United States (31a), and the mortality rates are as high as 80% (5, 11, 31). Aging increases both the incidence and the mortality rates due to AKI in both men and women. Despite the importance of the problem, the mechanisms responsible for AKI have not been completely elucidated.The incidence of acute renal failure in surgical patients is significantly higher in men than women (8,16,20). Animal studies have also reported sex differences in the adverse effects of ischemia reperfusion (I/R) of the kidney with males being more susceptible than females (18, 21). The mechanisms responsible for the sex differences in AKI in humans and the sex differences in animals are not clear.Reductions in serum testosterone in men have been shown in numerous studies to occur with chronic disease, such as heart disease, obesity, hypertension, and renal disease (2, 13, 15, 24). The association of reduction in testosterone with increased cardiovascular disease has lead investigators to suggest that it is the reduction in testosterone that may contribute to chronic disease states rather than that the chronic disease is the cause of the reduction in circulating testosterone levels (15). There is also evidence that acute conditions may reduce androgen levels. For example, Pugh et al. (23) and Tripathi and Hegde (30...

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“…In this sense, both estrogen receptor alpha (ER␣) deficiency and testosterone administration were associated with podocyte loss and augmented apoptosis in vivo (10). In type 1 diabetic castrated male rats, low dose of DHT attenuated, whereas high dose accentuated, the severity of several hallmarks of kidney disease such as glomerulosclerosis and tubulointerstitial fibrosis (11).…”

mentioning

confidence: 99%

Stable Isotope Labeling with Amino Acids (SILAC)-Based Proteomics of Primary Human Kidney Cells Reveals a Novel Link between Male Sex Hormones and Impaired Energy Metabolism in Diabetic Kidney Disease

Clotet

Soler

Riera

et al. 2017

Molecular & Cellular Proteomics

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Male sex predisposes to many kidney diseases. Considering that androgens exert deleterious effects in a variety of cell types within the kidney, we hypothesized that dihydrotestosterone (DHT) would alter the biology of the renal tubular cell by inducing changes in the proteome. We employed stable isotope labeling with amino acids (SILAC) in an indirect spike-in fashion to accurately quantify the proteome in DHT-and 17␤-estradiol (EST)-treated human proximal tubular epithelial cells (PTEC). Of the 5043 quantified proteins, 76 were differentially regulated. Biological processes related to energy metabolism were significantly enriched among DHT-regulated proteins. SILAC ratios of 3 candidates representing glycolysis, Nacetylglucosamine metabolism and fatty acid ␤-oxidation, namely glucose-6-phosphate isomerase (GPI), glucosamine-6-phosphate-N-acetyltransferase 1 (GNPNAT1), and mitochondrial trifunctional protein subunit alpha (HADHA), were verified in vitro. In vivo, renal GPI and HADHA protein expression was significantly increased in males. Furthermore, male sex was associated with significantly higher GPI, GNPNAT1, and HADHA kidney protein expression in two different murine models of diabetes. Enrichment analysis revealed a link between our DHTregulated proteins and oxidative stress within the diabetic kidney. This finding was validated in vivo, as we observed increased oxidative stress levels in control and diabetic male kidneys, compared with females. This in depth quantitative proteomics study of human primary PTEC response to sex hormone administration suggests that male sex hormone stimulation results in perturbed energy metabolism in kidney cells, and that this perturbation results in increased oxidative stress in the renal cortex. Chronic Kidney Disease (CKD)1 often results in irreversible deterioration of renal function that can progress to renal failure (1). Sex plays a relevant role in the progression and severity of many kidney diseases (2). At a clinical level, it is From the ‡Department

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Dose-dependent effects of dihydrotestosterone in the streptozotocin-induced diabetic rat kidney

Cited by 34 publications

References 29 publications

Gender-dependent effects of aging on the kidney

Gender-dependent effects of aging on the kidney

Protective role of testosterone in ischemia-reperfusion-induced acute kidney injury

Stable Isotope Labeling with Amino Acids (SILAC)-Based Proteomics of Primary Human Kidney Cells Reveals a Novel Link between Male Sex Hormones and Impaired Energy Metabolism in Diabetic Kidney Disease

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