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

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.

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

Frontiers in Immunology ◽

10.3389/fimmu.2021.669162 ◽

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

Scientific Reports ◽

10.1038/s41598-020-75025-5 ◽

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.

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

AJP Renal Physiology ◽

10.1152/ajprenal.00533.2018 ◽

2019 ◽

Vol 317 (3) ◽

pp. F616-F622 ◽

Cited By ~ 4

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.

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Quantified kidney echogenicity in mice with renal ischemia reperfusion injury: evaluation as a noninvasive biomarker of acute kidney injury

Medical Molecular Morphology ◽

10.1007/s00795-017-0157-8 ◽

2017 ◽

Vol 50 (3) ◽

pp. 161-169 ◽

Cited By ~ 3

Author(s):

Shinya Murata ◽

Noriyuki Sugiyama ◽

Kentaro Maemura ◽

Yoshinori Otsuki

Keyword(s):

Acute Kidney Injury ◽

Reperfusion Injury ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Kidney Injury ◽

Renal Ischemia ◽

Renal Ischemia Reperfusion Injury ◽

Noninvasive Biomarker

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In vivo transfection of NF-κB decoy oligodeoxynucleotides attenuate renal ischemia/reperfusion injury in rats

Kidney International ◽

10.1111/j.1523-1755.2004.00463.x ◽

2004 ◽

Vol 65 (3) ◽

pp. 834-845 ◽

Cited By ~ 109

Author(s):

Chang Chun Cao ◽

Xiao Qiang Ding ◽

Zhou Lou Ou ◽

Chun Feng Liu ◽

Peng Li ◽

...

Keyword(s):

Reperfusion Injury ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Renal Ischemia ◽

Renal Ischemia Reperfusion Injury ◽

In Vivo Transfection

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

International Journal of Molecular Sciences ◽

10.3390/ijms222010914 ◽

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.

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

10.1101/2021.09.01.458480 ◽

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.

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

AJP Renal Physiology ◽

10.1152/ajprenal.00088.2020 ◽

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.

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