Estrogen administered after cardiac arrest and cardiopulmonary resuscitation ameliorates acute kidney injury in a sex- and age-specific manner

Abstract

Introduction: There is a sex difference in the risk of ischemic acute kidney injury (AKI), and estrogen mediates the protective effect of female sex. We previously demonstrated that preprocedural chronic restoration of physiologic estrogen to ovariectomized female mice ameliorated AKI after cardiac arrest and cardiopulmonary resuscitation (CA/CPR). In the present study, we hypothesized that male mice and aged female mice would benefit from estrogen administration after CA/CPR. We tested the effect of estrogen in a clinically relevant manner by administrating it after CA/CPR. Methods: CA/CPR was performed in young (10-15 weeks), middle-aged (43-48 weeks), and aged (78-87 weeks) C57BL/6 male and female mice. Mice received intravenous 17β-estradiol or vehicle 15 min after resuscitation. Serum chemistries and unbiased stereological assessment of renal injury were completed 24 h after CA. Regional renal cortical blood flow was measured by a laser Doppler, and renal levels of estrogen receptor alpha (ERα) and G protein-coupled estrogen receptor (GPER) were evaluated with immunoblotting. Results: Post-arrest estrogen administration reduced injury in young males without significant changes in renal blood flow (percentage reduction compared with vehicle: serum urea nitrogen, 30 %; serum creatinine (sCr), 41 %; volume of necrotic tubules (VNT), 31 %; P < 0.05). In contrast, estrogen did not affect any outcomes in young females. In aged mice, estrogen significantly reduced sCr (80 %) and VNT (73 %) in males and VNT (51 %) in females. Serum estrogen levels in aged female mice after CA/CPR were the same as levels in male mice. With age, renal ERα was upregulated in females. Conclusions: Estrogen administration after resuscitation from CA ameliorates renal injury in young males and aged mice in both sexes. Because injury was small, young females were not affected. The protective effect of exogenous estrogen may be detectable with loss of endogenous estrogen in aged females and could be mediated by differences in renal ERs. Post-arrest estrogen administration is renoprotective in a sex-and age-dependent manner.

Aging Is Associated With Impaired Activation of Protein Homeostasis‐Related Pathways After Cardiac Arrest in Mice

“…Consistent with this finding, serum creatinine levels were significantly higher in aged versus young mice after CA/CPR (Figure 2D). Together, these data indicate that both brain and kidney sustained more severe damage in aged versus young mice in our CA/CPR model, which agrees with previous reports 15, 16…”

Visceral Adiposity Index and Lipid Accumulation Product Index: Two Alternate Body Indices to Identify Chronic Kidney Disease among the Rural Population in Northeast China

“…However, Palmer BF conducted a review showing that since estrogens could regulate adipose deposition and function, males and postmenopausal females tended to deposit more visceral fat, while premenopausal females accrued subcutaneous fat, leading to the classic body shape which has been highly correlated to an increased chronic disease risk [36]. Animal studies have demonstrated that estrogen exerts renoprotective effects after whole-body acute alternatives of hemodynamics and estrogen doses improved the renal outcome in male rats [37]. In contrast, women had higher values of VAI, LAPI and WHtR compared with men in our study population.…”

<p>Assessing Renal Microvascular Reactivity by Laser Speckle-Contrast Imaging in Angiotensin-II-Treated Mice</p>

“…Rodriguez-Porcel et al demonstrated impaired kidney response to vasodilators (acetylcholine and sodium nitroprusside), but they used electron-beam computed tomography, which is difficult to implement routinely. 20 LDF has been extensively used to assess renal microcirculation in mice in ischemiareperfusion, 21,22 preconditioning, 23 renal cryoinjury 24 or other models. 25 LASCA and LDF both use laser speckle patterns, but the analysis techniques differ.…”