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 Epoxide metabolites of arachidonate and docosahexaenoate function conversely in acute kidney injury involved in GSK3β signaling

2017 ◽  
Vol 114 (47) ◽  
pp. 12608-12613 ◽  
Author(s):  
Bing-Qing Deng ◽  
Ying Luo ◽  
Xin Kang ◽  
Chang-Bin Li ◽  
Christophe Morisseau ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Molecular Mechanisms ◽  
Glycogen Synthase ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Therapeutic Strategies ◽  
Epoxyeicosatrienoic Acid ◽  
Renal Tubular

Acute kidney injury (AKI) causes severe morbidity and mortality for which new therapeutic strategies are needed. Docosahexaenoic acid (DHA), arachidonic acid (ARA), and their metabolites have various effects in kidney injury, but their molecular mechanisms are largely unknown. Here, we report that 14 (15)-epoxyeicosatrienoic acid [14 (15)-EET] and 19 (20)-epoxydocosapentaenoic acid [19 (20)-EDP], the major epoxide metabolites of ARA and DHA, respectively, have contradictory effects on kidney injury in a murine model of ischemia/reperfusion (I/R)-caused AKI. Specifically, 14 (15)-EET mitigated while 19 (20)-EDP exacerbated I/R kidney injury. Manipulation of the endogenous 19 (20)-EDP or 14 (15)-EET by alteration of their degradation or biosynthesis with selective inhibitors resulted in anticipated effects. These observations are supported by renal histological analysis, plasma levels of creatinine and urea nitrogen, and renal NGAL. The 14 (15)-EET significantly reversed the I/R-caused reduction in glycogen synthase kinase 3β (GSK3β) phosphorylation in murine kidney, dose-dependently inhibited the hypoxia/reoxygenation (H/R)-caused apoptosis of murine renal tubular epithelial cells (mRTECs), and reversed the H/R-caused reduction in GSK3β phosphorylation in mRTECs. In contrast, 19 (20)-EDP dose-dependently promoted H/R-caused apoptosis and worsened the reduction in GSK3β phosphorylation in mRTECs. In addition, 19 (20)-EDP was more metabolically stable than 14 (15)-EET in vivo and in vitro. Overall, these epoxide metabolites of ARA and DHA function conversely in I/R-AKI, possibly through their largely different metabolic stability and their opposite effects in modulation of H/R-caused RTEC apoptosis and GSK3β phosphorylation. This study provides AKI patients with promising therapeutic strategies and clinical cautions.

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 Effect of Γ-aminobutyric acid on kidney injury induced by renal ischemia-reperfusion in male and female rats: Gender-related difference

2015 ◽  
Vol 4 (1) ◽  
pp. 158 ◽  
Author(s):  
Mehdi Nematbakhsh ◽  
Ramesh Monajemi ◽  
Ardeshir Talebi ◽  
Nahid Talebi ◽  
Soheyla Shirdavani ◽  
...  
Keyword(s):  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Renal Ischemia ◽  
Female Rats ◽  
Aminobutyric Acid ◽  
Male And Female ◽  
Related Difference ◽  
Male And Female Rats

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.

Protective Effect of PACAP on Ischemia/Reperfusion-Induced Kidney Injury of Male and Female Rats: Gender Differences

2018 ◽  
Vol 68 (3) ◽  
pp. 408-419 ◽  
Author(s):  
Eszter Laszlo ◽  
Tamas Juhasz ◽  
Adam Varga ◽  
Bernadett Czibere ◽  
Krisztina Kovacs ◽  
...  
Keyword(s):  
Gender Differences ◽  
Protective Effect ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Female Rats ◽  
Male And Female ◽  
Male And Female Rats

scholarly journals A1 adenosine receptor allosteric enhancer PD-81723 protects against renal ischemia-reperfusion injury

2012 ◽  
Vol 303 (5) ◽  
pp. F721-F732 ◽  
Author(s):  
Sang Won Park ◽  
Joo Yun Kim ◽  
Ahrom Ham ◽  
Kevin M. Brown ◽  
Mihwa Kim ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Side Effects ◽  
Proximal Tubule ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Wild Type ◽  
Renal Protection ◽  
Ischemic Acute Kidney Injury ◽  
Renal Tubular ◽  
Deficient Mice

Activation of A1 adenosine receptors (ARs) protects against renal ischemia-reperfusion (I/R) injury by reducing necrosis, apoptosis, and inflammation. However, extrarenal side effects (bradycardia, hypotension, and sedation) may limit A1AR agonist therapy for ischemic acute kidney injury. Here, we hypothesized that an allosteric enhancer for A1AR (PD-81723) protects against renal I/R injury without the undesirable side effects of systemic A1AR activation by potentiating the cytoprotective effects of renal adenosine generated locally by ischemia. Pretreatment with PD-81723 produced dose-dependent protection against renal I/R injury in A1AR wild-type mice but not in A1AR-deficient mice. Significant reductions in renal tubular necrosis, neutrophil infiltration, and inflammation as well as tubular apoptosis were observed in A1AR wild-type mice treated with PD-81723. Furthermore, PD-81723 decreased apoptotic cell death in human proximal tubule (HK-2) cells in culture, which was attenuated by a specific A1AR antagonist (8-cyclopentyl-1,3-dipropylxanthine). Mechanistically, PD-81723 induced sphingosine kinase (SK)1 mRNA and protein expression in HK-2 cells and in the mouse kidney. Supporting a critical role of SK1 in A1AR allosteric enhancer-mediated renal protection against renal I/R injury, PD-81723 failed to protect SK1-deficient mice against renal I/R injury. Finally, proximal tubule sphingosine-1-phosphate type 1 receptors (S1P1Rs) are critical for PD-81723-induced renal protection, as mice selectively deficient in renal proximal tubule S1P1Rs (S1P1Rflox/flox PEPCKCre/− mice) were not protected against renal I/R injury with PD-81723 treatment. Taken together, our experiments demonstrate potent renal protection with PD-81723 against I/R injury by reducing necrosis, inflammation, and apoptosis through the induction of renal tubular SK1 and activation of proximal tubule S1P1Rs. Our findings imply that selectively enhancing A1AR activation by locally produced renal adenosine may be a clinically useful therapeutic option to attenuate ischemic acute kidney injury without systemic side effects.

scholarly journals Mitochondrial transplantation by intra-arterial injection for acute kidney injury

2020 ◽  
Vol 319 (3) ◽  
pp. F403-F413 ◽  
Author(s):  
Ilias P. Doulamis ◽  
Alvise Guariento ◽  
Thomas Duignan ◽  
Takashi Kido ◽  
Arzoo Orfany ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Reperfusion Injury ◽  
Renal Cortex ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Renal Arteries ◽  
Histopathological Analysis ◽  
Renal Protection ◽  
Balloon Catheters

Acute kidney injury is a common clinical disorder and one of the major causes of morbidity and mortality in the postoperative period. In this study, the safety and efficacy of autologous mitochondrial transplantation by intra-arterial injection for renal protection in a swine model of bilateral renal ischemia-reperfusion injury were investigated. Female Yorkshire pigs underwent percutaneous bilateral temporary occlusion of the renal arteries with balloon catheters. Following 60 min of ischemia, the balloon catheters were deflated and animals received either autologous mitochondria suspended in vehicle or vehicle alone, delivered as a single bolus to the renal arteries. The injected mitochondria were rapidly taken up by the kidney and were distributed throughout the tubular epithelium of the cortex and medulla. There were no safety-related issues detected with mitochondrial transplantation. Following 24 h of reperfusion, estimated glomerular filtration rate and urine output were significantly increased while serum creatinine and blood urea nitrogen were significantly decreased in swine that received mitochondria compared with those that received vehicle. Gross anatomy, histopathological analysis, acute tubular necrosis scoring, and transmission electron microscopy showed that the renal cortex of the vehicle-treated group had extensive coagulative necrosis of primarily proximal tubules, while the mitochondrial transplanted kidney showed only patchy mild acute tubular injury. Renal cortex IL-6 expression was significantly increased in vehicle-treated kidneys compared with the kidneys that received mitochondrial transplantation. These results demonstrate that mitochondrial transplantation by intra-arterial injection provides renal protection from ischemia-reperfusion injury, significantly enhancing renal function and reducing renal damage.

scholarly journals Modulation of Endocannabinoids by Caloric Restriction Is Conserved in Mice but Is Not Required for Protection from Acute Kidney Injury

2021 ◽  
Vol 22 (11) ◽  
pp. 5485
Author(s):  
Karla Johanna Ruth Hoyer-Allo ◽  
Martin Richard Späth ◽  
Ruth Hanssen ◽  
Marc Johnsen ◽  
Susanne Brodesser ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Caloric Restriction ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Intraperitoneal Administration ◽  
Kidney Injury ◽  
Normal Serum ◽  
Renal Protection ◽  
Serum Samples ◽  
C Elegans

Acute kidney injury (AKI) is a frequent and critical complication in the clinical setting. In rodents, AKI can be effectively prevented through caloric restriction (CR), which has also been shown to increase lifespan in many species. In Caenorhabditis elegans (C. elegans), longevity studies revealed that a marked CR-induced reduction of endocannabinoids may be a key mechanism. Thus, we hypothesized that regulation of endocannabinoids, particularly arachidonoyl ethanolamide (AEA), might also play a role in CR-mediated protection from renal ischemia-reperfusion injury (IRI) in mammals including humans. In male C57Bl6J mice, CR significantly reduced renal IRI and led to a significant decrease of AEA. Supplementation of AEA to near-normal serum concentrations by repetitive intraperitoneal administration in CR mice, however, did not abrogate the protective effect of CR. We also analyzed serum samples taken before and after CR from patients of three different pilot trials of dietary interventions. In contrast to mice and C. elegans, we detected an increase of AEA. We conclude that endocannabinoid levels in mice are modulated by CR, but CR-mediated renal protection does not depend on this effect. Moreover, our results indicate that modulation of endocannabinoids by CR in humans may differ fundamentally from the effects in animal models.

Abstract 14991: Mitochondrial Transplantation by Intraarterial Injection Ameliorates Acute Kidney Injury

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Ilias P Doulamis ◽  
Alvise Guariento ◽  
Thomas Duignan ◽  
TAKASHI KIDO ◽  
Arzoo Orfany ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Renal Cortex ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Renal Arteries ◽  
Vehicle Group ◽  
Histopathological Analysis ◽  
Swine Model ◽  
Renal Protection ◽  
Balloon Catheters

Introduction: Acute kidney injury (AKI) is a common clinical disorder and one of the major causes of morbidity and mortality during the postoperative period. In this study, we investigated the safety and efficacy of autologous mitochondrial transplantation by intra-arterial injection for renal protection in a swine model of bilateral renal ischemia-reperfusion injury (IRI). Methods: Female Yorkshire pigs (n=12) underwent percutaneous bilateral temporary occlusion of the renal arteries with balloon-catheters. Following 60 minutes of ischemia, the balloon catheters were deflated and animals received either autologous mitochondria suspended in vehicle (n=6) or vehicle alone (n=6), delivered as a single bolus to the renal arteries. Results: Injected mitochondria were rapidly taken up by the kidney and were distributed throughout the tubular epithelium of the cortex and the medulla. Evaluation of plasma electrolytes, acid-base status, complete blood count and biochemical analysis did not reveal evidence of any adverse effects associated with mitochondrial transplantation. After 24 hours of reperfusion, eGFR and urine output were significantly increased (p<0.01) while plasma creatinine and BUN were significantly decreased (p<0.01) in pigs receiving mitochondria compared to vehicle (Figure 1). Gross anatomy, histopathological analysis, acute tubular necrosis scoring and transmission electron microscopy showed that the renal cortex of vehicle group had extensive coagulative necrosis of primarily proximal tubules, while mitochondrial transplanted kidneys showed only patchy mild acute tubular injury. Renal cortex IL-6 expression had a 3.5-fold significant increase (p<0.05) in vehicle kidneys compared to kidneys receiving mitochondrial transplantation. Conclusions: Mitochondrial transplantation by intra-arterial injection provides renal protection from IRI, significantly enhancing renal function and ameliorating AKI.

Sign in / Sign up

Export Citation Format

Share Document