Estrogen Is Renoprotective via  a Nonreceptor-dependent Mechanism after Cardiac Arrest In Vivo 

Abstract

Background Severe ischemia induces renal injury less frequently in women than men. In this study, cardiac arrest and cardiopulmonary resuscitation were used to assess whether estradiol is renoprotective via an estrogen receptor (ER)-dependent mechanism. Materials and Methods Male and female C57BL/6 and ER gene-deleted mice underwent 10 min of cardiac arrest followed by cardiopulmonary resuscitation. Serum chemistries and renal stereology were measured 24 h after arrest. Results Estrogen did not affect mean arterial pressure, regional renal cortical blood flow, and arterial blood gases. Hence, female kidneys were protected (mean ± SEM: blood urea nitrogen, 65 ± 21 vs.149 ± 27 mg/dl, P = 0.04; creatinine, 0.14 ± 0.05 vs. 0.73 ± 0.16 mg/dl, P = 0.01; volume of necrotic tubules, 7 ± 1% vs. 10 ± 0%, P = 0.04). Estrogen also reduced renal injury. In intact females (n = 5), ovariectomized/vehicle-treated (n = 8), and ovariectomized/estrogen-treated (n = 8) animals, blood urea nitrogen was 65 ± 21, 166 ± 28, and 50 ± 14 mg/dl (P = 0.002); creatinine was 0.14 ± 0.05, 0.74 ± 0.26, and 0.23 ± 0.27 mg/dl (P = 0.014); necrotic tubules were 2.5 ± 0.25%, 12.0 ± 1.9%, and 5.0 ± 1.6% (P = 0.004), respectively. In ER-α and ER-β gene-deleted mice and controls estradiol-reduced functional injury (blood urea nitrogen: estradiol 117 ± 71, vehicle 167 ± 56, P = 0.007; creatinine: estradiol 0.5 ± 0.5, vehicle 1.0 ± 0.4, P = 0.013), but the effect of estradiol was not different between ER-α or ER-β gene-deleted mice. Adding ICI 182,780 to estradiol did not alter injury. Conclusions In women, kidneys were protected from cardiac arrest through estrogen. Estradiol-mediated renoprotection was not affected by ER deletion or blockade. Estradiol is renoprotective after cardiac arrest. The results indicate that estradiol renoprotection is ER-α and ER-β independent.

Improved renal ischemia tolerance in females influences kidney transplantation outcomes

“…Multiple authors have described protective actions of estrogens in IRI in both male and female rodents, although in most reports the magnitude of this effect was smaller than that seen with the removal of testosterone (15,27,28). Moreover, renoprotection by estrogen is described in other forms of renal injury, including rat models of chronic allograft nephropathy (CAN) (15,24,25), age-related glomerular damage (29), and hypertensive nephrosclerosis (30).…”

Normothermic Cardiac Arrest and Cardiopulmonary Resuscitation: A Mouse Model of Ischemia-Reperfusion Injury

“…NGAL is massively upregulated in mouse urine after CA/CPR. Reprinted with permission from 14 . These findings are substantially similar to renal biopsy findings from humans who develop AKI, and unlike those produced by other animal models of AKI.…”

Effects of autologous SCF- and G-CSF-mobilized bone marrow stem cells on hypoxia-inducible factor-1 in rats with ischemia-reperfusion renal injury

“…Renal ischemia and direct kidney damage caused by renal toxic substances are the major causes of ATN, which results in renal ischemia and hypoxia. Tubular epithelial degeneration and necrosis often appear subsequently, and restoration of blood flow after ischemia and reperfusion may aggravate this injury (Hutchens et al, 2011). The treatment for clinical ischemia and/or hypoxia depends on the restoration of normal blood flow.…”