-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...

STAT3 is involved in protection of the heart provided by ischemic preconditioning. However, the role of this transcription factor in the heart in chronic stresses such as hypertension has not been defined. We assessed whether STAT3 is important in hypertension-induced cardiac remodeling using mice with reduced STAT3 activity due to a S727A mutation (SA/SA). Wild type (WT) and SA/SA mice received angiotensin (ANG) II or saline for 17 days. ANG II increased mean arterial and systolic pressure in SA/SA and WT mice, but cardiac levels of cytokines associated with heart failure were increased less in SA/SA mice. Unlike WT mice, hearts of SA/SA mice showed signs of developing systolic dysfunction as evidenced by reduction in ejection fraction and fractional shortening. In the left ventricle of both WT and SA/SA mice, ANG II induced fibrosis. However, fibrosis in SA/SA mice appeared more extensive and was associated with loss of myocytes. Cardiac hypertrophy as indexed by heart to body weight ratio and left ventricular anterior wall dimension during diastole was greater in WT mice. In WT+ANG II mice there was an increase in the mass of individual myofibrils. In contrast, cardiac myocytes of SA/SA+ANG II mice showed a loss in myofibrils and myofibrillar mass density was decreased during ANG II infusion. Our findings reveal that STAT3 transcriptional activity is important for normal cardiac myocyte myofibril morphology. Loss of STAT3 may impair cardiac function in the hypertensive heart due to defective myofibrillar structure and remodeling that may lead to heart failure.

Renal ischemia-reperfusion (I/R) in male rats causes reductions in plasma testosterone, and infusion of testosterone 3 h postreperfusion is protective. We tested the hypotheses that acute high doses of testosterone promote renal injury after I/R, and that acute low-dose testosterone is protective by the following: 1) increasing renal IL-10 and reducing TNF-α; 2) its effects on nitric oxide; and 3) reducing intrarenal T-cell infiltration. Rats were subjected to renal I/R, followed by intravenous infusion of vehicle or testosterone (20, 50, or 100 μg/kg) 3 h postreperfusion. Low-dose testosterone (20 μg/kg) reduced plasma creatinine, increased nitrate/nitrite excretion, increased intrarenal IL-10, and reduced intrarenal TNF-α, whereas 50 μg/kg testosterone failed to reduce plasma creatinine, increased IL-10, but failed to reduce TNF-α. A higher dose of testosterone (100 mg/kg) not only failed to reduce plasma creatinine, but significantly increased both IL-10 and TNF-α compared with other groups. Low-dose nitro-l-arginine methyl ester (1 mg·kg(-1)·day(-1)), given 2 days before I/R, prevented low-dose testosterone (20 μg/kg) from protecting against I/R injury, and was associated with lack of increase in intrarenal IL-10. Intrarenal CD4(+) and CD8(+) T cells were significantly increased with I/R, but were attenuated with low-dose testosterone, as were effector T helper 17 cells. The present studies suggest that acute, low-dose testosterone is protective against I/R AKI in males due to its effects on inflammation by reducing renal T-cell infiltration and by shifting the balance to favor anti-inflammatory cytokine production rather than proinflammatory cytokines.

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Smoking can worsen SP‐AngII induced chronic kidney disease (CKD). However, the mechanism behind this is equivocal. We hypothesized that NIC remodels the renal resistance vessels, worsening the hemodynamic parameters and hence contributes to the eventually deterioration of CKD. Male SD rats were pretreated for 12 days with NIC (12.5μg/ml) or vehicle (saccharine 2%) in water and then randomized into 4 groups: 1) Control (Cont), 2) NIC, 3) SP‐AngII (200ng/kg/min), 4) SP‐AngII + NIC. Each group received either vehicle or SP‐AngII by SQ osmotic minipumps, for an additional 22 days. Renal hemodynamics were measured in anesthetized animals, the kidneys harvested for morphometric analysis of afferent arteriole (Af‐Art) remodeling. Groups Proteinuria (mg/24 hrs) Medial Layer of Af‐Art (μm2) Lumen of Af‐Art (μm2) Media/Lumen ratio RVR (ml/min/mmHg) CRVR (TPU/mmHg) MVR (TPU/mmHg) Cont 19±1.2 124.3±12 144.5±6.3 1.13±0.1 16.2±2.5 2.6±0.2 4.5±0.2 NIC 34±4.4* 130.0±11 156.7±6 0.82±0.1 15.7±0.5 2.5±0.19 4.9±0.2 SP‐AngII 99±8.9† 253.1±11† 75.69±2.4† 3.55±0.2† 23±1.6† 3±0.17 6.6±0.2† SPAngII+NIC 150±6.5#† 321.3±10#† 31.53±2#† 11.98±1#† 32±2#† 3.6±0.2#† 9.5±0.4#† p< 0.05: * vs. Veh; # vs. SP‐AngII; † vs. NIC NIC worsened the SP‐AngII‐induced renal damage, and exacerbates the vascular resistance vessel remodeling that may contribute to the worsening hemodynamic parameters and eventually deterioration of Sp‐AngII‐ induced CKD.

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Renal I/R‐AKI results in systemic inflammation, including the heart. We recently reported that plasma TST is reduced during AKI, and its supplementation improves renal injury and inflammation by increasing cytoprotective factors. We now extended this study to test whether the lack of TST exacerbates I/R‐AKI and its cardiac abnormalities. Intact and castrated males (Cast) SD rats were treated with either vehicle or TST (20 ng/kg/min × 10min IV) given 3 hours after subjecting the rats to 40 min of bilateral renal I/R. After 48 hs, we harvested the kidney and the heart, and evaluated renal function and injury (PlCr ‐KIM‐1), cardiac stress (pro‐BNP), and cytoprotective factors (renal and cardiac heme oxygenase‐ HO‐1). PlCr mg/dl KIM‐1 pg/ml BNP ng/ug Renal HO‐1 ng/ml Cardiac HO‐1 ng/ml Sham 0.4 ±0.3 712 ±53 0.18 ±0.02 0.52±0.4 0.4 ±0.06 AKI 1.9 ±1.9* 4576 ±185* 3.8 ±0.1* 5.8±1.2* 5 ±0.1* AKI‐Cast 2.5 ±2.3& 8972 ±708& 4.4 ±1& 3±0.1& 3.7 ±0.1& AKI‐Cast‐TST 1.6 ±1# 2348 ±85 # 2.4 ±0.6# 4.4±0.2# 4.6 ±0.1# Data: Mean±SEM: p<0.05 vs Sham; vs AKI; vs AKI‐CT Lack of TST exacerbates I/R‐AKI and cardiac stress. Despite the increased injury, HO‐1 is decreased, suggesting that TST may be facilitating HO‐1 expression post AKI.