scholarly journals A mouse model of renal ischemia-reperfusion injury solely induced by cold ischemia

2019 ◽  
Vol 317 (3) ◽  
pp. F616-F622 ◽  
Author(s):  
Jin Wei ◽  
Yingliang Wang ◽  
Jie Zhang ◽  
Lei Wang ◽  
Liying Fu ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Mouse Model ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Renal Ischemia ◽  
Cold Ischemia ◽  
Preservation Solution ◽  
Renal Ischemia Reperfusion Injury

Transplanted kidneys usually experience several episodes of ischemia, including cold ischemia during allograft storage in preservation solution. However, previous studies focusing on cold renal ischemia were only carried out in vitro or ex vivo. In the present study, we developed and characterized an in vivo mouse model of renal ischemia-reperfusion injury (IRI) induced exclusively by cold ischemia. C57BL/6 mice underwent right kidney nephrectomy, and the left kidney was kept cool with circulating cold saline in a kidney cup, while body temperature was maintained at 37°C. We clamped the renal pedicle and flushed out the blood inside the kidney with cold saline via an opening on the renal vein. The severity of renal IRI was examined with different ischemic durations. We found that the mice with <2 h of cold ischemia exhibited no significant changes in renal function or histopathology; animals with 3 or 4 h of cold ischemia developed into mild to moderate acute kidney injury with characteristic features, including the elevation in plasma creatinine concentration and reduction in glomerular filtration rate and tubular necrosis, followed by a subsequent recovery. However, mice with 5 h of cold ischemia died in a few days with severe acute kidney injury. In summary, we generated a mouse model of renal IRI induced exclusively by cold ischemia, which mimics graft cold storage in preservation solution, and renal function can be evaluated in vivo.

scholarly journals Treprostinil, a prostacyclin analog, ameliorates renal ischemia–reperfusion injury: preclinical studies in a rat model of acute kidney injury

2020 ◽  
Author(s):  
Meiwen Ding ◽  
Evelyn Tolbert ◽  
Mark Birkenbach ◽  
Fatemeh Akhlaghi ◽  
Reginald Gohh ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Reperfusion Injury ◽  
Messenger Rna ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Renal Ischemia ◽  
Renal Ischemia Reperfusion Injury ◽  
Prostacyclin Analog

Abstract Graphical Abstract Background Renal ischemia–reperfusion injury (IRI) is a major factor causing acute kidney injury (AKI). No pharmacological treatments for prevention or amelioration of I/R-induced renal injury are available. Here we investigate the protective effects of treprostinil, a prostacyclin analog, against renal IRI in vivo. Methods Male Sprague Dawley rats were subjected to bilateral renal ischemia (45 min) followed by reperfusion for 1–168 h. Treprostinil (100 ng/kg/min) or placebo was administered subcutaneously for 18–24 h before ischemia. Results Treatment with treprostinil both significantly reduced peak elevation and accelerated the return to baseline levels for serum creatinine and blood urea nitrogen versus I/R-placebo animals following IRI. I/R-treprostinil animals exhibited reduced histopathological features of tubular epithelial injury versus I/R-placebo animals. IRI resulted in a marked induction of messenger RNA coding for kidney injury biomarkers, kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin and for pro-inflammatory cytokines chemokine (C-C motif) ligand 2, interleukin 1β, interleukin 6 and intracellular adhesion molecular 1 in animals treated with placebo only relative to sham controls. Upregulation of expression of all these genes was significantly suppressed by treprostinil. Treprostinil significantly suppressed the elevation in renal lipid peroxidation found in the I/R-placebo group at 1-h post-reperfusion. In addition, renal protein expression of cleaved poly(ADP-ribose) polymerase 1 and caspase-3, -8 and -9 in I/R-placebo animals was significantly inhibited by treprostinil. Conclusions This study demonstrates the efficacy of treprostinil in ameliorating I/R-induced AKI in rats by significantly improving renal function early post-reperfusion and by inhibiting renal inflammation and tubular epithelial apoptosis. Importantly, these data suggest that treprostinil has the potential to serve as a therapeutic agent to protect the kidney against IRI in vivo.

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.

scholarly journals NLRP2 is highly expressed and promotes apoptosis in a mouse model of kidney ischemia/reperfusion injury

2019 ◽  
Vol 17 ◽  
pp. 205873921985980 ◽  
Author(s):  
Xueyuan Yu ◽  
Xiumei Zhang ◽  
Zhao Hu
Keyword(s):  
Acute Kidney Injury ◽  
Mouse Model ◽  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Quantitative Polymerase Chain Reaction ◽  
Kidney Injury ◽  
Kidney Ischemia

The aim of this study was to investigate the role of nucleotide-binding oligomerization domain, leucine-rich repeat, and pyrin domain containing 2 (NLRP2) in kidney ischemia/reperfusion injury. A mouse model of acute kidney ischemia/reperfusion injury was established to conduct in vivo experiments. Oxygen–glucose deprivation (OGD) and cobalt chloride treatment of the HK-2 and glomerular endothelial cell (GENC) kidney cell lines were performed for the in vitro study. Reverse transcription–quantitative polymerase chain reaction, western blotting, and immunohistochemical staining were used to analyze NLRP2 expression levels. Knockdown of NLRP2 in cells was also performed, and cell apoptosis was detected using flow cytometry. NLRP2 was expressed in normal kidney tissues; however, its expression was significantly increased in the acute kidney injury model and in OGD-treated cells. Conversely, knockdown of NLRP2 reduced apoptosis of cells. These results suggested that NLRP2 was involved in kidney damage and may be an important target for treatment of acute kidney injury.

scholarly journals Systemic and sustained thioredoxin analogue prevents acute kidney injury and its-associated distant organ damage in renal ischemia reperfusion injury mice

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Kento Nishida ◽  
Hiroshi Watanabe ◽  
Masako Miyahisa ◽  
Yuto Hiramoto ◽  
Hiroto Nosaki ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Lung Injury ◽  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Expression System ◽  
Kidney Injury ◽  
Renal Ischemia ◽  
Tnf Α ◽  
Renal Ischemia Reperfusion Injury

AbstractThe mortality of patients with acute kidney injury (AKI) remains high due to AKI associated-lung injury. An effective strategy for preventing both AKI and AKI-associated lung injury is urgently needed. Thioredoxin-1 (Trx) is a redox-active protein that possesses anti-oxidative, anti-apoptotic and anti-inflammatory properties including modulation of macrophage migration inhibitory factor (MIF), but its short half-life limits its clinical application. Therefore, we examined the preventive effect of a long-acting Trx, which is a fusion protein of albumin and Trx (HSA-Trx), against AKI and AKI-associated lung injury. Recombinant HSA-Trx was expressed using a Pichia expression system. AKI-induced lung injury mice were generated by bilateral renal ischemia reperfusion injury (IRI). HSA-Trx administration attenuated renal IRI and its-associated lung injury. Both renal and pulmonary oxidative stress were suppressed by HSA-Trx. Moreover, HSA-Trx inhibited elevations of plasma IL-6 and TNF-α level, and suppressed IL-6–CXCL1/2-mediated neutrophil infiltration into lung and TNF-α-mediated pulmonary apoptosis. Additionally, HSA-Trx suppressed renal IRI-induced MIF expression in kidney and lung. Administration of HSA-Trx resulted in a significant increase in the survival rate of renal IRI mice. Collectively, HSA-Trx could have therapeutic utility in preventing both AKI and AKI-associated lung injury as a consequence of its systemic and sustained multiple biological action.

scholarly journals Mouse model of ischemic acute kidney injury: technical notes and tricks

2012 ◽  
Vol 303 (11) ◽  
pp. F1487-F1494 ◽  
Author(s):  
Qingqing Wei ◽  
Zheng Dong
Keyword(s):  
Acute Kidney Injury ◽  
Mouse Model ◽  
Drug Testing ◽  
Ischemia Reperfusion ◽  
Small Animal ◽  
Kidney Injury ◽  
Experimental Models ◽  
Renal Ischemia

Renal ischemia-reperfusion leads to acute kidney injury (AKI), a major kidney disease associated with an increasing prevalence and high mortality rates. A variety of experimental models, both in vitro and in vivo, have been used to study the pathogenic mechanisms of ischemic AKI and to test renoprotective strategies. Among them, the mouse model of renal clamping is popular, mainly due to the availability of transgenic models and the relatively small animal size for drug testing. However, the mouse model is generally less stable, resulting in notable variations in results. Here, we describe a detailed protocol of the mouse model of bilateral renal ischemia-reperfusion. We share the lessons and experiences gained from our laboratory in the past decade. We further discuss the technical issues that account for the variability of this model and offer relevant solutions, which may help other investigators to establish a well-controlled, reliable animal model of ischemic AKI.

scholarly journals P0511ENHANCER AND SUPER-ENHANCER DYNAMICS IN REPAIR AFTER ISCHEMIC ACUTE KIDNEY INJURY

2020 ◽  
Vol 35 (Supplement_3) ◽  
Author(s):  
Julia Wilflingseder ◽  
Michaela Willi ◽  
Hye Kyung Lee ◽  
Hannes Olauson ◽  
Jakub Jankowsky ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Transcription Factors ◽  
Small Molecule ◽  
Ischemia Reperfusion Injury ◽  
Specific Binding ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Kidney Cortex ◽  
Super Enhancer

Abstract Background and Aims The endogenous repair process of the mammalian kidney allows rapid recovery after acute kidney injury (AKI) through robust proliferation of tubular epithelial cells. There is currently limited understanding of which transcriptional regulators activate these repair programs and how transcriptional dysregulation leads to maladaptive repair. Here we investigate the existence of enhancer dynamics in the regenerating mouse kidney. Method RNA-seq and ChIP-seq (H3K27ac, H3K4m3, BRD4, POL2 and selected transcription factors) were performed on samples from repairing kidney cortex 2 days after ischemia/reperfusion injury (IRI) to identify activated genes, transcription factors, enhancer and super-enhancers associated with kidney repair. Further we investigated the role of super-enhancer activation in kidney repair through pharmacological BET inhibition using the small molecule JQ1 in vitro and in acute kidney injury models in vivo. Results Response to kidney injury leads to genome-wide alteration in enhancer repertoire in-vivo. We identified 16,781 enhancer sites (H3K27ac and BRD4 positive, H3K4me3 negative binding) active in SHAM and IRI samples; 6,512 lost and 9,774 gained after IRI. The lost and gained enhancer sites can be annotated to 62% and 63% of down- and up-regulated transcripts at day 2 after kidney injury, respectively. Super-enhancer analysis revealed 164 lost and 216 gained super-enhancer sites at IRI day 2. 385 super-enhancers maintain activity before and after injury. ChIP-seq profiles of selected transcription factors based on motif analysis show specific binding at corresponding enhancer sites. We observed lost enhancer binding of HNF4A and GR mainly at kidney related enhancer elements. In contrast, STAT3 showed increased binding at injury induces enhancer elements. No dynamic was observed for STAT5. Both transcription factor groups show corresponding mRNA changes after injury. Pharmacological inhibition of enhancer and super-enhancer activity by BRD4 inhibition (JQ1: 50mg/kg/day) before IRI leads to suppression of 40% of injury-induced transcripts associated with cell cycle regulation and significantly increased mortality between days 2 and 3 after AKI. Conclusion This is the first demonstration of enhancer and super-enhancer function in the repairing kidney. In addition, our data call attention to potential caveats for use of small molecule inhibitors of BET proteins that are currently being tested in clinical trials in cancer patients who are at risk for AKI. Our analyses of enhancer dynamics after kidney injury in vivo have the potential to identify new targets for therapeutic intervention.

Blockade of the G-CSF Receptor is Protective in a Mouse Model of Renal Ischemia Reperfusion Injury

2018 ◽  
Vol 102 ◽  
pp. S355
Author(s):  
Jennifer McRae ◽  
Anjan K. Bongoni ◽  
Evelyn K. Salvaris ◽  
Nella Fisicaro ◽  
Ingela Vikstrom ◽  
...  
Keyword(s):  
Mouse Model ◽  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Renal Ischemia ◽  
Renal Ischemia Reperfusion Injury

scholarly journals Blockade of the G-CSF Receptor Is Protective in a Mouse Model of Renal Ischemia–Reperfusion Injury

2020 ◽  
Vol 205 (5) ◽  
pp. 1433-1440
Author(s):  
Jennifer L. McRae ◽  
Ingela B. Vikstrom ◽  
Anjan K. Bongoni ◽  
Evelyn J. Salvaris ◽  
Nella Fisicaro ◽  
...  
Keyword(s):  
Mouse Model ◽  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Renal Ischemia ◽  
Renal Ischemia Reperfusion Injury

scholarly journals A mouse model of Townes-Brocks syndrome expressing a truncated mutant Sall1 protein is protected from acute kidney injury

2015 ◽  
Vol 309 (10) ◽  
pp. F852-F863 ◽  
Author(s):  
Sara Hirsch ◽  
Tarek El-Achkar ◽  
Lynn Robbins ◽  
Jeannine Basta ◽  
Monique Heitmeier ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Mouse Model ◽  
Congenital Anomalies ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Acute Injury ◽  
Null Alleles ◽  
Heme Oxygenase 1 ◽  
Adult Kidney

It has been postulated that developmental pathways are reutilized during repair and regeneration after injury, but functional analysis of many genes required for kidney formation has not been performed in the adult organ. Mutations in SALL1 cause Townes-Brocks syndrome (TBS) and nonsyndromic congenital anomalies of the kidney and urinary tract, both of which lead to childhood kidney failure. Sall1 is a transcriptional regulator that is expressed in renal progenitor cells and developing nephrons in the embryo. However, its role in the adult kidney has not been investigated. Using a mouse model of TBS ( Sall1 TBS), we investigated the role of Sall1 in response to acute kidney injury. Our studies revealed that Sall1 is expressed in terminally differentiated renal epithelia, including the S3 segment of the proximal tubule, in the mature kidney. Sall1 TBS mice exhibited significant protection from ischemia-reperfusion injury and aristolochic acid-induced nephrotoxicity. This protection from acute injury is seen despite the presence of slowly progressive chronic kidney disease in Sall1 TBS mice. Mice containing null alleles of Sall1 are not protected from acute kidney injury, indicating that expression of a truncated mutant protein from the Sall1 TBS allele, while causative of congenital anomalies, protects the adult kidney from injury. Our studies further revealed that basal levels of the preconditioning factor heme oxygenase-1 are elevated in Sall1 TBS kidneys, suggesting a mechanism for the relative resistance to injury in this model. Together, these studies establish a functional role for Sall1 in the response of the adult kidney to acute injury.

Sign in / Sign up

Export Citation Format

Share Document