Relaxin protects against renal ischemia-reperfusion injury

2013 ◽  
Vol 305 (8) ◽  
pp. F1169-F1176 ◽  
Author(s):  
Takuya Yoshida ◽  
Hiromichi Kumagai ◽  
Tetsuya Kohsaka ◽  
Naoki Ikegaya
Keyword(s):  
Structural Damage ◽  
Ischemia Reperfusion Injury ◽  
Apoptotic Cell ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Renal Ischemia ◽  
Male Rats ◽  
Semiquantitative Assessment ◽  
Cell Counts ◽  
Significant Difference

Relaxin, a pregnancy hormone, has antiapoptotic and anti-inflammatory properties. The aim of this study was to determine the effects of relaxin on ischemia-reperfusion (IR)-induced acute kidney injury. Male rats underwent unilateral nephrectomy and contralateral renal IR (45 min of renal pedicle clamping). Rats were divided into three groups: 1) sham group, 2) IR group, and 3) IR-RLX group (rats treated with relaxin before ischemia). In this group, relaxin was infused at 500 ng/h via subcutaneous osmotic minipump for 24 h beginning 2 h before renal ischemia. At 24 h after reperfusion, renal function was assessed and kidneys were removed for analysis. There was no significant difference in blood pressure among the three groups. IR increased plasma levels of creatinine and urea nitrogen, and relaxin provided protection against the increases in these two parameters. Relaxin significantly decreased plasma TNF-α levels and renal TNF receptor 1 mRNA expression, compared with the IR group. Semiquantitative assessment of the histological lesions showed marked structural damage in IR rats compared with the IR-RLX rats. RLX significantly reduced apoptotic cell counts compared with the IR group. Overexpression of caspase-3 observed in the IR kidneys was reduced in the IR-RLX group. The results demonstrated that relaxin provided protection against IR-induced renal injury by reducing apoptosis and inflammation.

scholarly journals The protective effects of pomegranate extracts against renal ischemia-reperfusion injury in male rats

2014 ◽  
Vol 6 (1) ◽  
pp. 46 ◽  
Author(s):  
AhmetA Sancaktutar ◽  
MehmetN Bodakci ◽  
NamıkK Hatipoglu ◽  
Kemal Basarılı ◽  
Haluk Soylemez ◽  
...  
Keyword(s):  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Renal Ischemia ◽  
Male Rats ◽  
Protective Effects ◽  
Renal Ischemia Reperfusion Injury

scholarly journals Targeting HIF-1α to Prevent Renal Ischemia-Reperfusion Injury: Does It Work?

2018 ◽  
Vol 2018 ◽  
pp. 1-7 ◽  
Author(s):  
Kapil Sethi ◽  
Kenny Rao ◽  
Damien Bolton ◽  
Oneel Patel ◽  
Joseph Ischia
Keyword(s):  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Tissue Injury ◽  
Ischemia Reperfusion ◽  
Arterial Occlusion ◽  
Small Animal ◽  
Kidney Injury ◽  
Renal Ischemia ◽  
Metabolic Adaptation ◽  
Critical Ischemia

Partial nephrectomy (open or minimally invasive) usually requires temporary renal arterial occlusion to limit intraoperative bleeding and improve access to intrarenal structures. This is a time-critical step due to the critical ischemia period of renal tissue. Prolonged renal ischemia may lead to irreversible nephron damage in the remaining tissue and, ultimately, chronic kidney disease. This is potentiated by the incompletely understood ischemia-reperfusion injury (IRI). A key mechanism in IRI prevention appears to be the upregulation of an intracellular transcription protein, Hypoxia-Inducible Factor (HIF). HIF mediates metabolic adaptation, angiogenesis, erythropoiesis, cell growth, survival, and apoptosis. Upregulating HIF-1α via ischemic preconditioning (IPC) or drugs that simulate hypoxia (hypoxia-mimetics) has been investigated as a method to reduce IRI. While many promising chemical agents have been trialed for the prevention of IRI in small animal studies, all have failed in human trials. The aim of this review is to highlight the techniques and drugs that target HIF-1α and ameliorate IRI associated with renal ischemia. Developing a technique or drug that could reduce the risk of acute kidney injury associated with renal IRI would have an immediate worldwide impact on multisystem surgeries that would otherwise risk ischemic tissue injury.

scholarly journals Arginase-2 mediates renal ischemia-reperfusion injury

2017 ◽  
Vol 313 (2) ◽  
pp. F522-F534 ◽  
Author(s):  
Wesley M. Raup-Konsavage ◽  
Ting Gao ◽  
Timothy K. Cooper ◽  
Sidney M. Morris ◽  
W. Brian Reeves ◽  
...  
Keyword(s):  
Reperfusion Injury ◽  
Blood Urea Nitrogen ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Renal Ischemia ◽  
Arginase Activity ◽  
Urea Nitrogen ◽  
The Impact ◽  
Novel Therapeutic

Novel therapeutic interventions for preventing or attenuating kidney injury following ischemia-reperfusion injury (IRI) remain a focus of significant interest. Currently, there are no definitive therapeutic or preventive approaches available for ischemic acute kidney injury (AKI). Our objective is to determine 1) whether renal arginase activity or expression is increased in renal IRI, and 2) whether arginase plays a role in development of renal IRI. The impact of arginase activity and expression on renal damage was evaluated in male C57BL/6J (wild type) and arginase-2 (ARG2)-deficient ( Arg2−/−) mice subjected to bilateral renal ischemia for 28 min, followed by reperfusion for 24 h. ARG2 expression and arginase activity significantly increased following renal IRI, paralleling the increase in kidney injury. Pharmacological blockade or genetic deficiency of Arg2 conferred kidney protection in renal IRI. Arg2−/− mice had significantly attenuated kidney injury and lower plasma creatinine and blood urea nitrogen levels after renal IRI. Blocking arginases using S-(2-boronoethyl)-l-cysteine (BEC) 18 h before ischemia mimicked arginase deficiency by reducing kidney injury, histopathological changes and kidney injury marker-1 expression, renal apoptosis, kidney inflammatory cell recruitment and inflammatory cytokines, and kidney oxidative stress; increasing kidney nitric oxide (NO) production and endothelial NO synthase (eNOS) phosphorylation, kidney peroxisome proliferator-activated receptor-γ coactivator-1α expression, and mitochondrial ATP; and preserving kidney mitochondrial ultrastructure compared with vehicle-treated IRI mice. Importantly, BEC-treated eNOS-knockout mice failed to reduce blood urea nitrogen and creatinine following renal IRI. These findings indicate that ARG2 plays a major role in renal IRI, via an eNOS-dependent mechanism, and that blocking ARG2 activity or expression could be a novel therapeutic approach for prevention of AKI.

scholarly journals Deletion of the Gamma Subunit of ENaC in Endothelial Cells Does Not Protect against Renal Ischemia Reperfusion Injury

2021 ◽  
Vol 22 (20) ◽  
pp. 10914
Author(s):  
Stephanie M. Mutchler ◽  
Mahpara Hasan ◽  
Donald E. Kohan ◽  
Thomas R. Kleyman ◽  
Roderick J. Tan
Keyword(s):  
Nitric Oxide ◽  
Endothelial Cells ◽  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Renal Ischemia ◽  
Α Subunit ◽  
Γ Subunit ◽  
Renal Ischemia Reperfusion Injury

Acute kidney injury due to renal ischemia-reperfusion injury (IRI) may lead to chronic or end stage kidney disease. A greater understanding of the cellular mechanisms underlying IRI are required to develop therapeutic options aimed at limiting or reversing damage from IRI. Prior work has shown that deletion of the α subunit of the epithelial Na+ channel (ENaC) in endothelial cells protects from IRI by increasing the availability of nitric oxide. While canonical ENaCs consist of an α, β, and γ subunit, there is evidence of non-canonical ENaC expression in endothelial cells involving the α subunit. We therefore tested whether the deletion of the γ subunit of ENaC also protects mice from IRI to differentiate between these channel configurations. Mice with endothelial-specific deletion of the γ subunit and control littermates were subjected to unilateral renal artery occlusion followed by 48 h of reperfusion. No significant difference was noted in injury between the two groups as assessed by serum creatinine and blood urea nitrogen, levels of specific kidney injury markers, and histological examination. While deletion of the γ subunit did not alter infiltration of immune cells or cytokine message, it was associated with an increase in levels of total and phosphorylated endothelial nitric oxide synthase (eNOS) in the injured kidneys. Our studies demonstrate that even though deletion of the γ subunit of ENaC may allow for greater activation of eNOS, this is not sufficient to prevent IRI, suggesting the protective effects of α subunit deletion may be due, in part, to other mechanisms.

scholarly journals Curcumin prevents renal oxidative stress and tissue damage induced by renal ischemia/reperfusion in rats

2018 ◽  
Vol 5 (10) ◽  
pp. 3192
Author(s):  
Nazile Erturk ◽  
Hulya Elbe ◽  
Zumrut Dogan ◽  
Serdar Aktas ◽  
Savas Demirbilek ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Renal Tissue ◽  
Renal Ischemia ◽  
Normal Morphology ◽  
Treatment Groups ◽  
Significant Difference ◽  
Intraperitoneal Dose ◽  
Dose Dependent

Background: There is increasing evidence to suggest that curcumin has antioxidant efficacy in renal ischemia reperfusion injury (IRI). However, it has not been investigated whether this effect is dose-dependent or not.  The aim of this study is to investigate the dose-dependent effect of curcumin on renal IRI in an experimental rat model.Methods: The rats (n=32) were separated into four groups: sham, I/R, I/R+CUR-50, I/R+CUR-100. Rats were subjected to renal ischemia by clamping bilateral renal pedicles for 60 min, and then reperfused for 3 h. Animals in treatment groups received 50 mg/kg/day and 100 mg/kg/day curcumin orally for 5 days before IRI, respectively. MDA, GSH, SOD, and CAT activities were determined in renal tissue. Renal tissue also evaluated histopathologically for mean histopathological damage score.Results: The mean MDA levels in the I/R+CUR-50 and I/R+CUR-100 groups were significantly decreased when compared with the I/R group (p=0.038 and p=0.016, respectively). SOD, CAT and GSH levels of all treatment groups were significantly increased in comparison to that of I/R group (p<0.05, for all). No statistically significant difference between treatment groups were detected (p>0.05). In histological examination, the rats treated with curcumin had nearly normal morphology of the kidney.Conclusions: Curcumin significantly ameliorates the damage of renal IRI by its antioxidant activity. We detected the highest intraperitoneal dose of curcumin reduced the IRI induced oxidative stress as 50 mg/kg per day.

scholarly journals Temporal and sex-dependent gene expression patterns in a renal ischemia-reperfusion injury and recovery pig model

2021 ◽  
Author(s):  
Stéphane Nemours ◽  
Luis Castro ◽  
Didac Ribatallada-Soriano ◽  
Maria Eugenia Semidey ◽  
Miguel Aranda ◽  
...  
Keyword(s):  
Sex Differences ◽  
Reperfusion Injury ◽  
Renal Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Renal Ischemia ◽  
Pig Model ◽  
Gene Sets ◽  
Renal Ischemia Reperfusion Injury

ABSTRACTMen are more prone to acute kidney injury (AKI) and chronic kidney disease (CKD), progressing to end-stage renal disease (ESRD) than women. Severity and capacity to regenerate after AKI are important determinants of CKD progression, and of patient morbidity and mortality in the hospital setting. To determine sex differences during injury and recovery we have generated a female and male renal ischemia/reperfusion injury (IRI) pig model, which represents a major cause of AKI. Although no differences were found in blood urea nitrogen (BUN) and serum creatinine (SCr) levels between both sexes, females exhibited higher mononuclear infiltrates at basal and recovery, while males showed more tubular damage at injury. Global transcriptomic analyses of kidney biopsies from our IRI pig model revealed a sexual dimorphism in the temporal regulation of genes and pathways relevant for kidney injury and repair, which was also detected in human samples. Enrichment analysis of gene sets revealed five temporal and four sexual patterns governing renal IRI and recovery. Overall, this study constitutes an extensive characterization of the time and sex differences occurring during renal IRI and recovery at gene expression level and offers a template of translational value for further study of sexual dimorphism in kidney diseases.AUTHOR SUMMARYKidneys’ correct functioning is essential for optimal body homeostasis, being their basic functions blood filtration and excretion of wastes and toxins. Inherited or acquired conditions can cause renal dysfunction requiring renal replacement therapy, which will affect patients’ life quality and survival. A major cause of kidney failure is the renal ischemia/reperfusion injury (IRI), which occurs in many clinical situations like kidney transplantation or aortic aneurysm surgery. Interestingly, men are more susceptible to IRI than women, being women more protected against kidney injury. However, the genetics regulating these sex differences in injury and renal repair remained unknown.Here, we provide a novel porcine model to study renal injury and recovery in both males and females. Using this model, we have identified the gene sets involved in renal injury and recovery processes. Moreover, global genetic analyses allowed us to discover the temporal and sex-dependent patterns that regulate those gene sets and, finally, kidney damage and repair. A relevant finding of our study is that males develop a feminized genetic profile during recovery, which may represent a survival mechanism to diminish the androgenic pro-damage effects on kidney cells. To sum up, our results provide novel sex-dependent targets to prevent renal injury and promote kidney recovery.

scholarly journals CBX7 suppression prevents ischemia-reperfusion injury-induced endoplasmic reticulum stress through the Nrf-2/HO-1 pathway

2020 ◽  
Vol 318 (6) ◽  
pp. F1531-F1538
Author(s):  
Ye Zhang ◽  
Jian-Jian Zhang ◽  
Xiu-Heng Liu ◽  
Lei Wang
Keyword(s):  
Acute Kidney Injury ◽  
Endoplasmic Reticulum ◽  
Endoplasmic Reticulum Stress ◽  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Renal Ischemia ◽  
Translation Initiation Factor ◽  
Heme Oxygenase 1

Renal ischemia-reperfusion injury (I/R) usually occurs in renal transplantation and partial nephrectomy, which could lead to acute kidney injury. However, the effective treatment for renal I/R still remains limited. In the present study, we investigated whether inhibition of chromobox 7 (CBX7) could attenuate renal I/R injury in vivo and in vitro as well as the potential mechanisms. Adult male mice were subjected to right renal ischemia and reperfusion for different periods, both with and without the CBX7 inhibitor UNC3866. In addition, human kidney cells (HK-2) were subjected to a hypoxia/reoxygenation (H/R) process for different periods, both with or without the CBX7 inhibitor or siRNA for CBX7. The results showed that expression of CBX7, glucose regulator protein-78 (GRP78), phosphorylated eukaryotic translation initiation factor-2α (p-eIF2α), and C/EBP homologous protein (CHOP) were increased after extension of I/R and H/R periods. Moreover, overexpression of CBX7 could elevate the expression of CBX7, GRP78, p-eIF2α, and CHOP. However, CBX7 inhibition with either UNC3866 or genetic knockdown led to reduced expression of GRP78, p-eIF2α, and CHOP through nuclear factor-erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 activation in I/R and H/R injury. Furthermore, ML385, the Nrf2 inhibitor, could elevate endoplasmic reticulum stress levels, abrogating the protective effects of UNC3866 against renal I/R injury. In conclusion, our results demonstrated that CBX7 inhibition alleviated acute kidney injury by preventing endoplasmic reticulum stress via the Nrf2/HO-1 pathway, indicating that CBX7 inhibitor could be a potential therapeutic target for renal I/R injury.

Abstract 494: P21 Plays a Protective Role Against Renal Ischemia Reperfusion Injury and is an Essential Factor for Ischemic Preconditioning

Hypertension ◽  
2012 ◽  
Vol 60 (suppl_1) ◽  
Author(s):  
Satoshi Nishioka ◽  
Daisuke Nakano ◽  
Kento Kitada ◽  
Hiroyuki Ohosaki ◽  
Tadashi Sofue ◽  
...  
Keyword(s):  
Ischemic Preconditioning ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Protective Role ◽  
Renal Ischemia ◽  
Histological Changes ◽  
Sham Surgery ◽  
Life Threatening

Background: We previously reported that various pathological conditions including high blood pressure increase p21 expression in the kidney; however, the functional importance of renal p21 up-regulation has not been clarified yet. In the present study, we evaluated the role of p21 in acute kidney injury, a life-threatening disease that can occur independently of the pathological background of patients (whether renal p21 is up-regulated or not). Methods and Results: The mice lacking functional p21 (p21-KO, n=9) and its wild-type control (WT, n=7) underwent a 45-min renal ischemia followed by a 24-h reperfusion (I/R). I/R significantly increased both mRNA expression and nuclear immunoreactivity of p21 in the kidney of WT compared with sham surgery (p21/β-actin, 1.28±0.23 vs. 0.57±0.15, respectively, P<0.05). I/R injury analyzed by blood urea nitrogen (BUN) and kidney histological changes were exacerbated in p21-KO mice (BUN: WT; 103.8±4.6 mg/dL, p21-KO; 127.7±5.2 mg/dL, P<0.05). The results suggest that p21 plays a protective role against I/R injury. Therefore, we next examined whether p21 is also associated with the protective effect of ischemic preconditioning (IPC), which is an established method of attenuating the I/R injury. IPC (4 sets of a 5-min ischemia and a 5-min reperfusion) clearly improved the I/R injury in WT (BUN: sham; 87.7±22.0 mg/dL, IPC; 39.0±2.3 mg/dL, n=3 and n=7, respectively, P<0.05), whereas there was no difference in the I/R injury in p21-KO mice (BUN: sham; 136.5±13.6 mg/dL, IPC; 127.9±6.9 mg/dL, n=5 and n=8, respectively). IPC increased the renal expression of p21 prior to I/R compared with sham surgery (p21/β-actin: 1.07±0.08 vs. 0.26±0.05 fold, respectively, P<0.05). Conclusion: Renal p21 plays a protective role against I/R injury and is necessary for the beneficial effect of renal IPC.

scholarly journals Protective Effect of CXCR3+CD4+CD25+Foxp3+Regulatory T Cells in Renal Ischemia-Reperfusion Injury

2015 ◽  
Vol 2015 ◽  
pp. 1-8 ◽  
Author(s):  
Cao Jun ◽  
Li Qingshu ◽  
Wei Ke ◽  
Li Ping ◽  
Dong Jun ◽  
...  
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Renal Ischemia ◽  
Tubular Necrosis ◽  
Renal Ischemia Reperfusion Injury ◽  
Histology Score

Regulatory T cells (Tregs) suppress excessive immune responses and are potential therapeutic targets in autoimmune disease and organ transplantation rejection. However, their role in renal ischemia-reperfusion injury (IRI) is unclear. Levels of Tregs and expression of CXCR3 in Tregs were analyzed to investigate their function in the early phase of renal IRI. Mice were randomly divided into Sham, IRI, and anti-CD25 (PC61) + IRI groups. The PC61 + IRI group was established by i.p. injection of PC61 monoclonal antibody (mAb) to deplete Tregs before renal ischemia. CD4+CD25+Foxp3+Tregs and CXCR3 on Tregs were analyzed by flow cytometry. Blood urea nitrogen (BUN), serum creatinine (Scr) levels, and tubular necrosis scores, all measures of kidney injury, were greater in the IRI group than in the Sham group. Numbers of Tregs were increased at 72 h after reperfusion in kidney. PC61 mAb preconditioning decreased the numbers of Tregs and aggravated kidney injury. There was no expression of CXCR3 on Tregs in normal kidney, while it expanded at 72 h after reperfusion and inversely correlated with BUN, Scr, and kidney histology score. This indicated that recruitment of Tregs into the kidney was related to the recovery of renal function after IRI and CXCR3 might be involved in the migration of Tregs.

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