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 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.

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.

DPP4 inhibition improves functional outcome after renal ischemia-reperfusion injury

2012 ◽  
Vol 303 (5) ◽  
pp. F681-F688 ◽  
Author(s):  
Lorenzo L. F. Glorie ◽  
Anja Verhulst ◽  
Veerle Matheeussen ◽  
Lesley Baerts ◽  
Joanna Magielse ◽  
...  
Keyword(s):  
Reperfusion Injury ◽  
Mrna Expression ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Renal Ischemia ◽  
Terminal Deoxynucleotidyl Transferase ◽  
Protective Effects ◽  
Dipeptidyl Peptidase 4 ◽  
Dpp4 Inhibition

Dipeptidyl peptidase 4 (DPP4) is an exopeptidase which modulates the function of its substrates, among which are insulin-releasing incretins. DPP4 inhibitors are currently used to improve glucose tolerance in type 2 diabetes patients. Inhibition of DPP4 exhibits protective effects on ischemia-reperfusion injury (IRI) of the heart and lung. As DPP4 and its substrates are also expressed in the kidney, we studied the effect of the DPP4 inhibitor vildagliptin on the outcome of IRI-induced acute kidney injury in rats in a model of 30-min unilateral renal ischemia, followed by contralateral nephrectomy. Saline, 1, or 10 mg/kg vildagliptin (VG1/VG10) was administered intravenously 15 min before the surgery. Animals were euthanized after 2, 12, amd 48 h of reperfusion. DPP4 inhibition resulted in a significant dose-dependent decrease in serum creatinine (1.31 ± 0.32 and 0.70 ± 0.19 mg/dl for VG1 and VG10, respectively, vs. 1.91 ± 0.28 mg/dl for controls at 12 h; P < 0.01). Tubular morphology (PAS-PCNA) revealed significantly reduced tubular necrosis at 12 h (62.1 ± 18.0 and 77.5 ± 22.0% in VG10 and saline, respectively). VG did not affect regeneration but decreased apoptosis, as shown by twofold decreased Bax/Bcl-2 mRNA expression and a threefold decrease in apoptotic bodies on terminal deoxynucleotidyl transferase dUTP nick-end labeling-stained sections. VG treatment significantly reduced serum malondialdehyde twofold in both VG1- and VG10-treated ischemic and sham-operated animals compared with controls and also resulted in a significant decrease in mRNA expression of the proinflammatory marker CXCL10 at 2 h of reperfusion. Through a mechanism yet to be fully understood, VG treatment results in a functional protection of the kidney against IRI. This protection was associated with antiapoptotic, immunological, and antioxidative changes.

scholarly journals C-reactive protein exacerbates renal ischemia-reperfusion injury

2013 ◽  
Vol 304 (11) ◽  
pp. F1358-F1365 ◽  
Author(s):  
Melissa A. Pegues ◽  
Mark A. McCrory ◽  
Abolfazl Zarjou ◽  
Alexander J. Szalai
Keyword(s):  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Renal Ischemia ◽  
Alternative Activation ◽  
Pcr Analysis ◽  
C Reactive Protein ◽  
Reactive Protein ◽  
Renal Ischemia Reperfusion Injury

Renal ischemia-reperfusion injury (IRI) is a common cause of acute kidney injury (AKI), occurring with hypotension and cardiovascular surgery and inevitably during kidney transplantation. Mortality from AKI is high due to incomplete knowledge of the pathogenesis of IRI and the lack of an effective therapy. Inflammation accompanies IRI and increases the blood level of C-reactive protein (CRP), a biomarker of worsened outcomes in AKI. To test if CRP is causal in AKI we subjected wild-type mice (WT) and human CRP transgenic mice (CRPtg) to bilateral renal IRI (both pedicles clamped for 30 min at 37°C then reperfused for 24 h). Serum human CRP level was increased approximately sixfold after IRI in CRPtg (10.62 ± 1.31 μg/ml at baseline vs. 72.01 ± 9.41 μg/ml at 24 h) but was not elevated by sham surgery wherein kidneys were manipulated but not clamped. Compared with WT, serum creatinine, urine albumin, and histological evidence of kidney damage were increased after IRI in CRPtg mice. RT-PCR analysis of mRNA isolated from whole kidneys of CRPtg and WT subjected to IRI revealed that in CRPtg kidneys 1) upregulation of markers of macrophage classical activation (M1 markers) was blunted, 2) downregulation of markers of macrophage alternative activation (M2 markers) was more robust, and 3) expression of the activating receptor FcγRI was increased. Our finding that CRP exacerbates IRI-induced AKI, perhaps by shifting the balance of macrophage activation and FcγR expression towards a detrimental portfolio, might make CRP a promising therapeutic target for the treatment of AKI.

scholarly journals Acute Kidney Injury Induced Lupus Exacerbation Through the Enhanced Neutrophil Extracellular Traps (and Apoptosis) in Fcgr2b Deficient Lupus Mice With Renal Ischemia Reperfusion Injury

2021 ◽  
Vol 12 ◽  
Author(s):  
Wilasinee Saisorn ◽  
Supichcha Saithong ◽  
Pornpimol Phuengmaung ◽  
Kanyarat Udompornpitak ◽  
Thansita Bhunyakarnjanarat ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Neutrophil Extracellular Traps ◽  
Renal Ischemia ◽  
Extracellular Traps ◽  
Renal Ischemia Reperfusion Injury ◽  
Syk Inhibitor

Renal ischemia is the most common cause of acute kidney injury (AKI) that might be exacerbate lupus activity through neutrophil extracellular traps (NETs) and apoptosis. Here, the renal ischemia reperfusion injury (I/R) was performed in Fc gamma receptor 2b deficient (Fcgr2b-/-) lupus mice and the in vitro experiments. At 24 h post-renal I/R injury, NETs in peripheral blood neutrophils and in kidneys were detected using myeloperoxidase (MPO), neutrophil elastase (NE) and citrullinated histone H3 (CitH3), as well as kidney apoptosis (activating caspase-3), which were prominent in Fcgr2b-/- mice more compared to wild-type (WT). After 120 h renal-I/R injury, renal NETs (using MPO and NE) were non-detectable, whereas glomerular immunoglobulin (Ig) deposition and serum anti-dsDNA were increased in Fcgr2b-/- mice. These results imply that renal NETs at 24 h post-renal I/R exacerbated the lupus nephritis at 120 h post-renal I/R injury in Fcgr2b-/- lupus mice. Furthermore, a Syk inhibitor attenuated NETs, that activated by phorbol myristate acetate (PMA; a NETs activator) or lipopolysaccharide (LPS; a potent inflammatory stimulator), more prominently in Fcgr2b-/- neutrophils than the WT cells as determined by dsDNA, PAD4 and MPO. In addition, the inhibitors against Syk and PAD4 attenuated lupus characteristics (serum creatinine, proteinuria, and anti-dsDNA) in Fcgr2b-/- mice at 120 h post-renal I/R injury. In conclusion, renal I/R in Fcgr2b-/- mice induced lupus exacerbation at 120 h post-I/R injury partly because Syk-enhanced renal NETs led to apoptosis-induced anti-dsDNA, which was attenuated by a Syk inhibitor.

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