scholarly journals Female and male mice have differential longterm cardiorenal outcomes following a matched degree of ischemia–reperfusion acute kidney injury

2022 ◽  
Vol 12 (1) ◽  
Author(s):  
Danielle E. Soranno ◽  
Peter Baker ◽  
Lara Kirkbride-Romeo ◽  
Sara A. Wennersten ◽  
Kathy Ding ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Acute Kidney Injury ◽  
Mitochondrial Function ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Cardiovascular Outcomes ◽  
Male Mice ◽  
Male And Female ◽  
Female Mice

AbstractAcute kidney injury (AKI) is common in patients, causes systemic sequelae, and predisposes patients to long-term cardiovascular disease. To date, studies of the effects of AKI on cardiovascular outcomes have only been performed in male mice. We recently demonstrated that male mice developed diastolic dysfunction, hypertension and reduced cardiac ATP levels versus sham 1 year after AKI. The effects of female sex on long-term cardiac outcomes after AKI are unknown. Therefore, we examined the 1-year cardiorenal outcomes following a single episode of bilateral renal ischemia–reperfusion injury in female C57BL/6 mice using a model with similar severity of AKI and performed concomitantly to recently published male cohorts. To match the severity of AKI between male and female mice, females received 34 min of ischemia time compared to 25 min in males. Serial renal function, echocardiograms and blood pressure assessments were performed throughout the 1-year study. Renal histology, and cardiac and plasma metabolomics and mitochondrial function in the heart and kidney were evaluated at 1 year. Measured glomerular filtration rates (GFR) were similar between male and female mice throughout the 1-year study period. One year after AKI, female mice had preserved diastolic function, normal blood pressure, and preserved levels of cardiac ATP. Compared to males, females demonstrated pathway enrichment in arginine metabolism and amino acid related energy production in both the heart and plasma, and glutathione in the plasma. Cardiac mitochondrial respiration in Complex I of the electron transport chain demonstrated improved mitochondrial function in females compared to males, regardless of AKI or sham. This is the first study to examine the long-term cardiac effects of AKI on female mice and indicate that there are important sex-related cardiorenal differences. The role of female sex in cardiovascular outcomes after AKI merits further investigation.

scholarly journals Sex diversity in proximal tubule and endothelial gene expression in mice with ischemic acute kidney injury

2020 ◽  
Vol 134 (14) ◽  
pp. 1887-1909
Author(s):  
Jose L. Viñas ◽  
Christopher J. Porter ◽  
Adrianna Douvris ◽  
Matthew Spence ◽  
Alex Gutsol ◽  
...  
Keyword(s):  
Gene Expression ◽  
Acute Kidney Injury ◽  
Hepatitis A Virus ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Ischemic Injury ◽  
Gene Profiling ◽  
Specific Gene ◽  
Male And Female ◽  
Female Mice

Abstract Female sex protects against development of acute kidney injury (AKI). While sex hormones may be involved in protection, the role of differential gene expression is unknown. We conducted gene profiling in male and female mice with or without kidney ischemia–reperfusion injury (IRI). Mice underwent bilateral renal pedicle clamping (30 min), and tissues were collected 24 h after reperfusion. RNA-sequencing (RNA-Seq) was performed on proximal tubules (PTs) and kidney endothelial cells. Female mice were resistant to ischemic injury compared with males, determined by plasma creatinine and neutrophil gelatinase-associated lipocalin (NGAL), histologic scores, neutrophil infiltration, and extent of apoptosis. Sham mice had sex-specific gene disparities in PT and endothelium, and male mice showed profound gene dysregulation with ischemia–reperfusion compared with females. After ischemia PTs from females exhibited smaller increases compared with males in injury-associated genes lipocalin-2 (Lcn2), hepatitis A virus cellular receptor 1 (Havcr1), and keratin 18 (Krt18), and no up-regulation of SRY-Box transcription factor 9 (Sox9) or keratin 20 (Krt20). Endothelial up-regulation of adhesion molecules and cytokines/chemokines occurred in males, but not females. Up-regulated genes in male ischemic PTs were linked to tumor necrosis factor (TNF) and Toll-like receptor (TLR) pathways, while female ischemic PTs showed up-regulated genes in pathways related to transport. The data highlight sex-specific gene expression differences in male and female PTs and endothelium before and after ischemic injury that may underlie disparities in susceptibility to AKI.

scholarly journals Adolescent intermittent ethanol exposure induces sex-dependent divergent changes in ethanol drinking and motor activity in adulthood in C57BL/6J mice

2020 ◽  
Author(s):  
Antoniette M. Maldonado-Devincci ◽  
Joseph G. Makdisi ◽  
Andrea M. Hill ◽  
Renee C. Waters ◽  
Nzia I. Hall ◽  
...  
Keyword(s):  
Open Field ◽  
Ethanol Consumption ◽  
Ethanol Exposure ◽  
Male Mice ◽  
Open Field Behavior ◽  
Male And Female ◽  
Female Mice ◽  
Binge Ethanol Exposure ◽  
Binge Ethanol

AbstractWith alcohol readily accessible to adolescents, its consumption leads to many adverse effects, including impaired learning, attention, and behavior. Adolescents report higher rates of binge drinking compared to adults. Adolescents are also more prone to substance use disorder during adulthood due to physiological changes during the adolescent developmental period. We used C57BL/6J male and female mice to investigate the long-lasting impact of binge ethanol exposure during adolescence on voluntary ethanol intake and open field behavior during later adolescence and in young adulthood. The present set of experiments were divided into four stages: (1) chronic intermittent vapor inhalation exposure, (2) abstinence, (3) voluntary ethanol intake, and (4) open field behavioral testing. During adolescence, male and female mice were exposed to air or ethanol using an intermittent vapor inhalation with repeated binge pattern ethanol exposure from postnatal day (PND) 28–42. Following this, mice underwent abstinence during late adolescence from PND 43–49 (Experiment 1) or PND 43–69 (Experiment 2). Beginning on PND 49–76 (Experiment 1) or PND 70–97 (Experiment 2), mice were assessed for intermittent voluntary ethanol consumption using a two-bottle drinking procedure over 28 days. Male mice that were exposed to ethanol during adolescence showed increased ethanol consumption during later adolescence (Experiment 1) and in emerging adulthood (Experiment 2), while the female mice showed decreased ethanol consumption. These data demonstrate a sexually divergent shift in ethanol consumption following binge ethanol exposure during adolescence and differences in open field behavior. These data highlight sex-dependent vulnerability to developing substance use disorders in adulthood.Significance StatementCurrently, it is vital to determine the sex-dependent impact of binge alcohol exposure during adolescence, given that until recently females have largely been ignored. Here we show that adolescent male mice that are exposed to binge ethanol during adolescence show long-term changes in behavior in adulthood. In contrast, female mice show a transient decrease in ethanol consumption in adulthood and decreased motor activity spent in the center zone of the open field test. Male mice appear to be more susceptible to the long-term changes in ethanol consumption following binge ethanol exposure during adolescence.

Abstract 655: Ischemia-induced Epoxyeicosatrienoic Acid Release Protects Female Rats From Acute Kidney Injury

Hypertension ◽  
2012 ◽  
Vol 60 (suppl_1) ◽  
Author(s):  
Duska Dragun ◽  
Uwe Hoff ◽  
Maximilian Blum ◽  
Gordana Bubalo ◽  
Mandy Fechner ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Creatinine Clearance ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Female Rats ◽  
Epoxyeicosatrienoic Acid ◽  
Renal Protection ◽  
Sham Control ◽  
Male And Female ◽  
Enhanced Production

Females are naturally protected against ischemia/reperfusion (I/R)-induced acute kidney injury (AKI) in various clinical and experimental settings. However, the underlying mechanisms are unknown. We hypothesized that female protection may be conferred by enhanced production of cytochrome P450 (CYP)-dependent epoxyeicosatrienoic acids (EETs) that promote vasodilation as well as antiinflammatory and antiapoptotic pathways in the kidney. To test this hypothesis, we first analyzed the renal CYP-eicosanoid profile by liquid chromatography tandem mass spectrometry in male and female Lewis rats. Ischemia was induced through 45 min of left renal vessel clamping after right nephrectomy (n=6-8 per group). In non-ischemic controls, male and female kidneys stored almost identical amounts of EETs as well as 20-hydroxyeicosatetraenoic acid (20-HETE), both predominantly esterified into phospholipids, under basal non-ischemic conditions. 45 min of ischemia induced a massive release of EETs from membrane stores in females but not males. The free renal EET-levels reached 70.2±20.1 in females compared to only 4.6±1.3 ng/g in males. After ischemia, the ratio of free EETs to free 20-HETE was about 1:1 in females and 1:3 in males. Next, we proved the functional importance of EETs in renal protection by pretreating males with a synthetic EET-agonist (12-HUDE) and females with a selective EET-antagonist (14,15-EEZE-mSI). As analyzed two days after reperfusion, the EET-agonist protected males against loss of creatinine clearance (1.03±0.18 vs. 0.26±0.02 ml/min, p<0.01 vs. vehicle, compared to 1.28±0.06 ml/min in sham control). Females were rendered susceptible to I/R-injury by the EET-antagonist (creatinine clearance: 0.25±0.05 vs. 0.67±0.04; p<0.01 vs. vehicle, compared to 0.81±0.04 ml/min in sham control). Changes in inflammatory cell infiltration and tubular apoptosis paralleled these effects on renal function. Our results indicate that female rats are protected against renal I/R-injury by enhanced ischemia-induced EET-release and demonstrate that renal protection can be transferred to males using synthetic EET-agonists.

scholarly journals Acute kidney injury during pregnancy leads to increased sFlt-1 and sEng and decreased renal T regulatory cells in pregnant rats with HELLP syndrome

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Jamie Szczepanski ◽  
Shauna-Kay Spencer ◽  
Ashley Griffin ◽  
Teylor Bowles ◽  
Jan Michael Williams ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Acute Kidney Injury ◽  
Hellp Syndrome ◽  
T Regulatory Cells ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Regulatory Cells ◽  
T Helper 17 ◽  
Pregnant Rats ◽  
The Impact

Abstract Background The incidence of acute kidney injury (AKI) during pregnancy precedes a high maternal mortality rate of 20–40%. AKI during pregnancy has multiple etiologies; however, the more common are maternal hypertensive disorders, which include preeclampsia and HELLP (hemolysis, elevated liver enzyme, low platelet) syndrome. Therefore, we sought to assess the impact of AKI on blood pressure, kidney injury, and anti-angiogenic factors during pregnancies with and without HELLP syndrome. Methods On gestational day (GD) 12, mini-osmotic pumps were inserted into a subset of normal pregnant (NP) rats infusing 4.7 μg/kg soluble fms-like tyrosine kinase-1 (sFlt-1) and 7 μg/kg soluble endoglin (sEng) to induce HELLP syndrome. On GD18, the renal pedicles were occluded for 45 min to induce AKI via bilateral ischemia reperfusion in a subset of NP (n = 18) or HELLP (n = 20) rats. Control NP (n = 20) and HELLP (n = 20) rats underwent a SHAM surgery on GD18. Plasma, urine, and maternal organs were saved for further analysis. Renal injury was assessed via renal histopathology, glomerular filtration rate (GFR), T cell infiltration, and assessment of kidney injury molecule-1 (KIM-1) and neutrophil gelatinase-associated lipocalin (NGAL). Data was measured via two-way analysis of variance with Tukey’s test for post hoc analysis. Results Blood pressures were increased in HELLP+AKI rats (p = 0.0001); both NP+AKI and HELLP+AKI rats had increased lactate dehydrogenase (p < 0.0001) and aspartate aminotransferase levels (p < 0.0001), and decreased platelet levels (p < 0.001) vs. NP rats. HELLP+AKI (p = 0.002) and HELLP rats (p = 0.0002) had evidence of renal fibrosis vs. NP rats. GFR was decreased in HELLP+AKI (p = 0.01) rats vs. NP rats. Urinary KIM-1 was increased in NP+AKI rats vs. NP (p = 0.003) and HELLP rats (p = 0.01). HELLP+AKI rats had increased urinary KIM-1 vs. NP (p = 0.0008) and HELLP rats (p = 0.004) and increased NGAL vs. HELLP rats (p = 0.002). HELLP+AKI rats had increased sFlt-1 (p = 0.009) vs. NP rats. NP+AKI (p = 0.02) and HELLP+AKI (p = 0.007) rats had increased sEng vs. NP rats. CD3+CD4+ T cells were significantly increased in HELLP+AKI rats vs. NP (p = 0.0002) and NP+AKI (p = 0.05) rats. T regulatory cells were significantly decreased in HELLP+AKI (p = 0.03) and NP+AKI (p = 0.02) rats vs. NP rats; there were no changes between groups in T helper 17 cells (p = 0.34). Conclusion The findings in this study suggest that AKI during pregnancy contributes to increased blood pressure and biochemical markers for HELLP syndrome, creates an anti-angiogenic imbalance, and exacerbates kidney injury as shown on histopathology, GFR, and kidney injury markers.

scholarly journals Early antihypertensive treatment and ischemia-induced acute kidney injury

2020 ◽  
Vol 319 (4) ◽  
pp. F563-F570
Author(s):  
Robert Greite ◽  
Katja Derlin ◽  
Bennet Hensen ◽  
Anja Thorenz ◽  
Song Rong ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Acute Kidney Injury ◽  
Antihypertensive Treatment ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Renal Perfusion ◽  
Renal Outcome ◽  
Major Surgery ◽  
Mesangial Matrix ◽  
Matrix Expansion

Acute kidney injury (AKI) frequently complicates major surgery and can be associated with hypertension and progress to chronic kidney disease, but reports on blood pressure normalization in AKI are conflicting. In the present study, we investigated the effects of an angiotensin-converting enzyme inhibitor, enalapril, and a soluble epoxide hydrolase inhibitor, 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl)urea (TPPU), on renal inflammation, fibrosis, and glomerulosclerosis in a mouse model of ischemia-reperfusion injury (IRI)-induced AKI. Male CD1 mice underwent unilateral IRI for 35 min. Blood pressure was measured by tail cuff, and mesangial matrix expansion was quantified on methenamine silver-stained sections. Renal perfusion was assessed by functional MRI in vehicle- and TPPU-treated mice. Immunohistochemistry was performed to study the severity of AKI and inflammation. Leukocyte subsets were analyzed by flow cytometry, and proinflammatory cytokines were analyzed by quantitative PCR. Plasma and tissue levels of TPPU and lipid mediators were analyzed by liquid chromatography mass spectrometry. IRI resulted in a blood pressure increase of 20 mmHg in the vehicle-treated group. TPPU and enalapril normalized blood pressure and reduced mesangial matrix expansion. However, inflammation and progressive renal fibrosis were severe in all groups. TPPU further reduced renal perfusion on days 1 and 14. In conclusion, early antihypertensive treatment worsened renal outcome after AKI by further reducing renal perfusion despite reduced glomerulosclerosis.

scholarly journals Gender differences control the susceptibility to ER stress-induced acute kidney injury

2013 ◽  
Vol 304 (7) ◽  
pp. F875-F882 ◽  
Author(s):  
Rawad Hodeify ◽  
Judit Megyesi ◽  
Adel Tarcsafalvi ◽  
Hossam I. Mustafa ◽  
Nang San Hti Lar Seng ◽  
...  
Keyword(s):  
Gender Differences ◽  
Acute Kidney Injury ◽  
Er Stress ◽  
Kidney Function ◽  
Kidney Injury ◽  
Proximal Tubules ◽  
Male Mice ◽  
Outer Cortex ◽  
Treated Male ◽  
Female Mice

Endoplasmic reticulum (ER) stress contributes to acute kidney injury induced by several causes. Kidney dysfunction was shown to be influenced by gender differences. In this study we observed differences in the severity of kidney injury between male and female mice in response to tunicamycin, an ER stress agent. Tunicamycin-treated male mice showed a severe decline in kidney function and extensive kidney damage of proximal tubules in the kidney outer cortex (S1 and S2 segments). Interestingly, female tunicamycin-treated mice did not show a decline in kidney function, and their kidneys showed damage localized primarily to proximal tubules in the inner cortex (S3 segment). Protein markers of ER stress, glucose-regulated protein, and X-box binding protein 1 were also more elevated in male mice. Similarly, the induction of apoptosis was higher in tunicamycin-treated male mice, as measured by the activation of Bax and caspase-3. Testosterone administered to female mice before tunicamycin resulted in a phenotype similar to male mice with a comparable decline in renal function, tissue morphology, and induction of ER stress markers. We conclude that kidneys of male mice are much more susceptible to ER stress-induced acute kidney injury than those of females. Moreover, this sexual dimorphism could provide an interesting model to study the relation between kidney function and injury to a specific nephron segment.

scholarly journals Long-term outcomes in mouse models of ischemia-reperfusion-induced acute kidney injury

2019 ◽  
Vol 317 (4) ◽  
pp. F1068-F1080 ◽  
Author(s):  
Lauren Scarfe ◽  
Anna Menshikh ◽  
Emily Newton ◽  
Yuantee Zhu ◽  
Rachel Delgado ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Acute Kidney Injury ◽  
Kidney Disease ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Mouse Strains ◽  
Preclinical Studies ◽  
Long Term Outcomes

Severe acute kidney injury has a high mortality and is a risk factor for progressive chronic kidney disease. None of the potential therapies that have been identified in preclinical studies have successfully improved clinical outcomes. This failure is partly because animal models rarely reflect the complexity of human disease: most preclinical studies are short term and are commonly performed in healthy, young, male mice. Therapies that are effective in preclinical models that share common clinical features seen in patients with acute kidney injury, including genetic diversity, different sexes, and comorbidities, and evaluate long-term outcomes are more likely to predict success in the clinic. Here, we evaluated susceptibility to chronic kidney disease after ischemia-reperfusion injury with delayed nephrectomy by monitoring long-term functional and histological responses to injury. We defined conditions required to induce long-term postinjury renal dysfunction and fibrosis without increased mortality in a reproducible way and evaluate effect of mouse strains, sexes, and preexisting diabetes on these responses.

Does long-term high-altitude exposure reduce myocardial injury and incidence of acute kidney injury following cardiac surgery? A propensity score matched study

2021 ◽  
Author(s):  
Mengxue Liu ◽  
Man Wang ◽  
Jia Huang ◽  
Zuojia Zeng ◽  
Keli Huang ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Cardiac Surgery ◽  
Propensity Score ◽  
High Altitude ◽  
Lower Incidence ◽  
Myocardial Injury ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Altitude Exposure

Abstract Objective Chronic high-altitude exposure has been shown to reduce ischemia-reperfusion injury in animal experiments. The objective was to evaluate the clinical protective effect of long-term high-altitude hypoxic exposure for patients undergoing cardiac surgery with cardiopulmonary bypass. Methods In this retrospective cohort study, data from patients who underwent cardiac procedures between January 2013 and December 2019 at a single center was collected. Patients were divided into highlander group (> 2500 m) and lowlander group (< 1500 m) according to the altitude of their residence. A propensity-score-matched analysis was performed to estimate the association of long-term high-altitude exposure and cardiac surgery outcomes. Results In a total of 2085 patients, 128 highlander patients were matched to 248 lowlander patients. The levels of CK-MB and hs-TnI upon arrival at the intensive care unit were lower in the highlander group compared to the lowlander group [70.6 U/L (56.0, 92.6) vs 85.0 U/L (68.5, 113.5), P < 0.001; 6.1 ng/mL (3.3,11.2) vs 7.9 ng/mL (3.6, 14.1), P = 0.011, respectively]. The highlander group also had a lower incidence of acute kidney injury (13.3% vs 21.8%, P = 0.046). The in-hospital mortality in the highlander group was lower than in the lowlander group without statistical significance (0.8% vs 4.0%, P = 0.107). Conclusions Long-term high-altitude exposure was associated with less myocardial injury and a lower incidence of acute kidney injury after cardiac surgery.

scholarly journals Complement Initiation Varies by Sex in Intestinal Ischemia Reperfusion Injury

2021 ◽  
Vol 12 ◽  
Author(s):  
Miaomiao Wu ◽  
Jennifer M. Rowe ◽  
Sherry D. Fleming
Keyword(s):  
Complement Activation ◽  
Intestinal Ischemia ◽  
Tissue Injury ◽  
Ischemia Reperfusion ◽  
Critical Role ◽  
Dependent Manner ◽  
Male Mice ◽  
Male And Female ◽  
Female Mice ◽  
Intestinal Ischemia Reperfusion

Intestinal ischemia reperfusion (IR)-induced tissue injury represents an acute inflammatory response with significant morbidity and mortality. The mechanism of IR-induced injury is not fully elucidated, but recent studies suggest a critical role for complement activation and for differences between sexes. To test the hypothesis that complement initiation differs by sex in intestinal IR, we performed intestinal IR on male and female WT C57B6L/, C1q-/-, MBL-/-, or properdin (P)-/- mice. Intestinal injury, C3b and C5a production and ex vivo secretions were analyzed. Initial studies demonstrated a difference in complement mRNA and protein in male and female WT mice. In response to IR, male C1q-, MBL- and P-deficient mice sustained less injury than male WT mice. In contrast, only female MBL-/- mice sustained significantly less injury than female wildtype mice. Importantly, wildtype, C1q-/- and P-/- female mice sustained significant less injury than the corresponding male mice. In addition, both C1q and MBL expression and deposition increased in WT male mice, while only elevated MBL expression and deposition occurred in WT female mice. These data suggested that males use both C1q and MBL pathways, while females tend to depend on lectin pathway during intestinal IR. Females produced significantly less serum C5a in MBL-/- and P-/- mice. Our findings suggested that complement activation plays a critical role in intestinal IR in a sex-dependent manner.

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