miR-182-5p and miR-378a-3p regulate ferroptosis in I/R-induced renal injury

Abstract Renal tubular cell death is the key factor of the pathogenesis of ischemia/reperfusion (I/R) kidney injury. Ferroptosis is a type of regulated cell death (RCD) found in various diseases. However, the underlying molecular mechanisms related to ferroptosis in renal I/R injury remain unclear. In the present study, we investigated the regulatory role of microRNAs on ferroptosis in I/R-induced renal injury. We established the I/R-induced renal injury model in rats, and H/R induced HK-2 cells injury in vitro. CCK-8 was used to measure cell viability. Fe2+ and ROS levels were assayed to evaluate the activation of ferroptosis. We performed RNA sequencing to profile the miRNAs expression in H/R-induced injury and ferroptosis. Western blot analysis was used to detect the protein expression. qRT-PCR was used to detect the mRNA and miRNA levels in cells and tissues. We further used luciferase reporter assay to verify the direct targeting effect of miRNA. We found that ischemia/reperfusion-induced ferroptosis in rat’s kidney. We identified that miR-182-5p and miR-378a-3p were upregulated in the ferroptosis and H/R-induced injury, and correlates reversely with glutathione peroxidases 4 (GPX4) and solute carrier family 7 member 11 (SLC7A11) expression in renal I/R injury tissues, respectively. In vitro studies showed that miR-182-5p and miR-378a-3p induced ferroptosis in cells. We further found that miR-182-5p and miR-378a-3p regulated the expression of GPX4 and SLC7A11 negatively by directly binding to the 3′UTR of GPX4 and SLC7A11 mRNA. In vivo study showed that silencing miR-182-5p and miR-378a-3p alleviated the I/R-induced renal injury in rats. In conclusion, we demonstrated that I/R induced upregulation of miR-182-5p and miR-378a-3p, leading to activation of ferroptosis in renal injury through downregulation of GPX4 and SLC7A11.

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

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1705615114 ◽

2017 ◽

Vol 114 (47) ◽

pp. 12608-12613 ◽

Cited By ~ 20

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.

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Protective effect of glycine on renal injury induced by ischemia-reperfusion in vivo

AJP Renal Physiology ◽

10.1152/ajprenal.00011.2001 ◽

2002 ◽

Vol 282 (3) ◽

pp. F417-F423 ◽

Cited By ~ 41

Author(s):

Ming Yin ◽

Zhi Zhong ◽

Henry D. Connor ◽

Hartwig Bunzendahl ◽

William F. Finn ◽

...

Keyword(s):

Renal Injury ◽

Cell Injury ◽

Ischemia Reperfusion Injury ◽

Interstitial Fibrosis ◽

Ischemia Reperfusion ◽

Control Group ◽

Renal Tubular Cell ◽

Sprague Dawley

Although glycine prevents renal tubular cell injury in vitro, its effect in vivo is not clear. The purpose of this study was to investigate whether a bolus injection of glycine given before reperfusion plus continuous dietary supplementation afterward would reduce renal injury caused by ischemia-reperfusion. Female Sprague-Dawley rats received a semisynthetic powdered diet containing 5% glycine and 15% casein (glycine group) or 20% casein (control group). Two days later, renal ischemia was produced by cross-clamping the left renal vessels for 15 min, followed by reperfusion. The right kidney was removed before reperfusion. The postischemic glomerular filtration rate (GFR) showed that renal function was less impaired and recovered more quickly in rats receiving glycine. For example, at day 7, GFR in controls (0.31 ± 0.03 ml · min−1 · 100 g−1) was about one-half that of glycine-treated rats (0.61 ± 0.06 ml · min−1 · 100 g−1, P < 0.05). Furthermore, tubular injury and cast formation observed in controls was minimized by glycine (pathology score, 3.2 ± 0.4 vs. 1.0 ± 0.4, P < 0.05). Urinary lactate dehydrogenase (LDH) concentration was elevated by ischemia-reperfusion in the control group (260 ± 22 U/l), but values were significantly lower by about fourfold (60 ± 30 U/l) in glycine-fed rats. Similarly, free radical production in urine was significantly lower in glycine-treated animals. Importantly, on postischemic day 1, binding of pimonidazole, an in vivo hypoxia marker, was increased in the outer medulla in controls; however, this phenomenon was prevented by glycine. Two weeks later, mild leukocyte infiltration and interstitial fibrosis were still observed in controls, but not in kidneys from glycine-treated rats. In conclusion, these results indicate that administration of glycine indeed reduces mild ischemia-reperfusion injury in the kidney in vivo, in part by decreasing initial damage and preventing chronic hypoxia.

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Trehalose attenuates renal ischemia-reperfusion injury by enhancing autophagy and inhibiting oxidative stress and inflammation

AJP Renal Physiology ◽

10.1152/ajprenal.00568.2019 ◽

2020 ◽

Vol 318 (4) ◽

pp. F994-F1005

Author(s):

Suwen Liu ◽

Yunwen Yang ◽

Huiping Gao ◽

Ning Zhou ◽

Peipei Wang ◽

...

Keyword(s):

Oxidative Stress ◽

Renal Function ◽

Renal Injury ◽

Ischemia Reperfusion ◽

Kidney Injury ◽

Renal Ischemia ◽

Renal Histology ◽

Hypoxia Reoxygenation

Renal ischemia-reperfusion (IR) injury is one of the most common acute kidney injuries, but there is still a lack of effective treatment in the clinical setting. Trehalose (Tre), a natural disaccharide, has been demonstrated to protect against oxidative stress, inflammation, and apoptosis. However, whether it could protect against IR-induced renal injury needs to be investigated. In an in vivo experiment, C57BL/6J mice were pretreated with or without Tre (2 g/kg) through a daily single intraperitoneal injection from 3 days before renal IR surgery. Renal function, apoptosis, oxidative stress, and inflammation were analyzed to evaluate kidney injury. In an in vitro experiment, mouse proximal tubular cells were treated with or without Tre under a hypoxia/reoxygenation condition. Western blot analysis, autophagy flux detection, and apoptosis assay were performed to evaluate the level of autophagy and antiapoptotic effect of Tre. The in vivo results showed that the renal damage induced by IR was ameliorated by Tre treatment, as renal histology and renal function were improved and the enhanced protein levels of kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin were blocked. Moreover, autophagy was activated by Tre pretreatment along with inhibition of the IR injury-induced apoptosis, oxidative stress, and inflammation. The in vitro results showed that Tre treatment activated autophagy and protected against hypoxia/reoxygenation-induced tubular cell apoptosis and oxidative stress. Our results demonstrated that Tre protects against IR-induced renal injury, possibly by enhancing autophagy and blocking oxidative stress, inflammation, and apoptosis, suggesting its potential use for the clinical treatment of renal IR injury.

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Therapeutic Challenge of Minicircle Vector Encoding Klotho in Animal Model

American Journal of Nephrology ◽

10.1159/000499863 ◽

2019 ◽

Vol 49 (5) ◽

pp. 413-424 ◽

Cited By ~ 4

Author(s):

Yoo Jin Shin ◽

Kang Luo ◽

Yi Quan ◽

Eun Jeong Ko ◽

Byung Ha Chung ◽

...

Keyword(s):

Renal Injury ◽

Ischemia Reperfusion Injury ◽

Therapeutic Potential ◽

Ischemia Reperfusion ◽

Kidney Injury ◽

Acute Ischemia ◽

Klotho Protein ◽

Self Production ◽

In Cells

Background: Klotho treatment is a promising approach against kidney injury, but its clinical application is still undetermined. We developed a novel strategy to allow self-production of Klotho protein, using minicircle (MC) technology, and evaluated its feasibility in therapeutic Klotho delivery. Methods: We engineered MC vectors to carry cassette sequences of Klotho and verified the self-production of Klotho protein from in HEK293T cells. We evaluated the location and persistence of delivered MC in vivo, and the duration of Klotho protein production from MCs by serial measurement of Klotho protein in blood. We subsequently evaluated the therapeutic potential of Klotho-encoding MCs in experimental model of renal injury. Results: We confirmed the production of Klotho from MC by its significant availability in cells transfected with the MC, as well as in its conditioned medium, compared to that in cells transfected with parent vector. MCs were delivered in vivo by hydrodynamic injection via tail vein. After a single injection of MCs, red fluorescence protein was detected until 30 days in liver, and Klotho protein was maintained until 10 days in the blood, suggesting the production of Klotho protein from MCs via protein synthesis machinery in liver. Therapeutic effect of MC was confirmed by functional and histological improvement seen in mouse model of acute ischemia-reperfusion injury and unilateral ureteral obstruction. Conclusion: Together, these findings implied that self-generated Klotho protein, using MC technology, is functionally active and relevant as a therapeutic approach in renal injury.

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Apigenin Nanoparticle Attenuates Renal Ischemia/Reperfusion Inflammatory Injury by Regulation of miR-140-5p/CXCL12/NF-κB Signaling Pathway

Journal of Biomedical Nanotechnology ◽

10.1166/jbn.2021.3010 ◽

2021 ◽

Vol 17 (1) ◽

pp. 64-77

Author(s):

Xiangfei He ◽

Yibo Wen ◽

Qingwei Wang ◽

Yan Wang ◽

Guoxian Zhang ◽

...

Keyword(s):

Signaling Pathway ◽

Nuclear Translocation ◽

Ischemia Reperfusion ◽

Kidney Injury ◽

Luciferase Reporter ◽

Inflammatory Injury ◽

Positive Effects ◽

Hypoxia Reoxygenation

Apigenin as a natural flavonoid product has been proved previously to play a renoprotective effect during ischemia/reperfusion injury (IRI), but the particular mechanisms involving the positive effects of apigenin remain totally unclear. The study investigated apigenin's roles and underlying biological mechanisms in IR-induced acute kidney injury (AKI). Thirty-six mice received a right nephrectomy and clamping of the left renal artery for 30 minutes, and then perfusion for 24 h. Apigenin was loaded onto a biodegradable polymer carrier (nanoparticle) to enhance its bioavailability. Mice were subjected to intraperitoneally injection with apigenin (5, 10 or 20 mg/kg) for 24 h before surgery. For in vitro experiments, mouse renal tubular epithelial cells (mRTECs) and miR-140-5p mimic/inhibitor transfected mRTECs were subjected to hypoxia/reoxygenation in the presence or absence of apigenin. In vitro, we uncovered that hypoxia/reoxygenation stimulation caused inflammatory injury in mRTECs. Apigenin reduced the hypoxia/reoxygenation-induced cell inflammatory injury and NF- B p65 nuclear translocation from cytoplasm and activation. Moreover, apigenin reduced hypoxia/reoxygenationtriggered miR-140-5p down-regulation. What's more, the luciferase reporter system revealed that miR-140-5p negatively regulates CXCL12, which is its direct target of action. CXCL12 exhibited an inhibitory effect on the apigenin-induced inactivation of NF- B signaling pathway. Furthermore, we observed that apigenin pretreatment attenuated the IR-triggered up-regulation of serum creatinine and blood urea nitrogen, elevation of pro-inflammatory cytokines secretion and tubular cell apoptosis, enhancement of CXCL12 and decline of miR-140-5p in vivo. Our studies show that apigenin protects against IR-triggered renal cell inflammatory injury in vivo and in vitro by miR-140-5p up-regulation and CXCL12 downregulation via quenching the NF- B pathway activation. Apigenin may be an encouraging therapeutic agent for patients with IR-associated kidney injury.

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Gpr97 Exacerbates AKI by Mediating Sema3A Signaling

Journal of the American Society of Nephrology ◽

10.1681/asn.2017080932 ◽

2018 ◽

Vol 29 (5) ◽

pp. 1475-1489 ◽

Cited By ~ 8

Author(s):

Wei Fang ◽

Ziying Wang ◽

Quanxin Li ◽

Xiaojie Wang ◽

Yan Zhang ◽

...

Keyword(s):

Renal Injury ◽

Acute Tubular Necrosis ◽

Molecular Mechanisms ◽

Rna Binding ◽

Ischemia Reperfusion ◽

Luciferase Reporter ◽

Induced Expression ◽

Tubular Necrosis ◽

Deficient Mice

Background G protein-coupled receptors (GPCRs) participate in a variety of physiologic functions, and several GPCRs have critical physiologic and pathophysiologic roles in the regulation of renal function. We investigated the role of Gpr97, a newly identified member of the adhesion GPCR family, in AKI.Methods AKI was induced by ischemia–reperfusion or cisplatin treatment in Gpr97-deficient mice. We assessed renal injury in these models and in patients with acute tubular necrosis by histologic examination, and we conducted microarray analysis and in vitro assays to determine the molecular mechanisms of Gpr97 function.Results Gpr97 was upregulated in the kidneys from mice with AKI and patients with biopsy-proven acute tubular necrosis compared with healthy controls. In AKI models, Gpr97-deficient mice had significantly less renal injury and inflammation than wild-type mice. Gpr97 deficiency also attenuated the AKI-induced expression of semaphorin 3A (Sema3A), a potential early diagnostic biomarker of renal injury. In NRK-52E cells subjected to oxygen–glucose deprivation, siRNA-mediated knockdown of Gpr97 further increased the expression of survivin and phosphorylated STAT3 and reduced toll-like receptor 4 expression. Cotreatment with recombinant murine Sema3A protein counteracted these effects. Finally, additional in vivo and in vitro studies, including electrophoretic mobility shift assays and luciferase reporter assays, showed that Gpr97 deficiency attenuates ischemia–reperfusion-induced expression of the RNA-binding protein human antigen R, which post-transcriptionally regulates Sema3A expression.Conclusions Gpr97 is an important mediator of AKI, and pharmacologic targeting of Gpr97-mediated Sema3A signaling at multiple levels may provide a novel approach for the treatment of AKI.

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microRNA-377 Signaling Modulates Anticancer Drug-Induced Cardiotoxicity in Mice

Frontiers in Cardiovascular Medicine ◽

10.3389/fcvm.2021.737826 ◽

2021 ◽

Vol 8 ◽

Author(s):

John Henderson ◽

Praveen K. Dubey ◽

Mallikarjun Patil ◽

Sarojini Singh ◽

Shubham Dubey ◽

...

Keyword(s):

Cell Death ◽

Rna Sequencing ◽

Molecular Mechanisms ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Drug Induced ◽

Chemotherapy Agent

Doxorubicin (DOX, an anthracycline) is a widely used chemotherapy agent against various forms of cancer; however, it is also known to induce dose-dependent cardiotoxicity leading to adverse complications. Investigating the underlying molecular mechanisms and strategies to limit DOX-induced cardiotoxicity might have potential clinical implications. Our previous study has shown that expression of microRNA-377 (miR-377) increases in cardiomyocytes (CMs) after cardiac ischemia-reperfusion injury in mice, but its specific role in DOX-induced cardiotoxicity has not been elucidated. In the present study, we investigated the effect of anti-miR-377 on DOX-induced cardiac cell death, remodeling, and dysfunction. We evaluated the role of miR-377 in CM apoptosis, its target analysis by RNA sequencing, and we tested the effect of AAV9-anti-miR-377 on DOX-induced cardiotoxicity and mortality. DOX administration in mice increases miR-377 expression in the myocardium. miR-377 inhibition in cardiomyocyte cell line protects against DOX-induced cell death and oxidative stress. Furthermore, RNA sequencing and Gene Ontology (GO) analysis revealed alterations in a number of cell death/survival genes. Intriguingly, we observed accelerated mortality and enhanced myocardial remodeling in the mice pretreated with AAV9-anti-miR-377 followed by DOX administration as compared to the AAV9-scrambled-control-pretreated mice. Taken together, our data suggest that in vitro miR-377 inhibition protects against DOX-induced cardiomyocyte cell death. On the contrary, in vivo administration of AAV9-anti-miR-377 increases mortality in DOX-treated mice.

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MiR-485-5p Promotes Neuron Survival through Mediating Rac1/Notch2 Signaling Pathway after Cerebral Ischemia/Reperfusion

Current Neurovascular Research ◽

10.2174/1567202617666200415154822 ◽

2020 ◽

Vol 17 (3) ◽

pp. 259-266 ◽

Cited By ~ 2

Author(s):

Xuan Chen ◽

Sumei Zhang ◽

Peipei Shi ◽

Yangli Su ◽

Dong Zhang ◽

...

Keyword(s):

Oxidative Stress ◽

Cell Viability ◽

Therapeutic Option ◽

Ischemia Reperfusion ◽

Glucose Deprivation ◽

Small Gtpase ◽

Luciferase Reporter ◽

Pathological Feature ◽

In Cells

Objective: Ischemia-reperfusion (I/R) injury is a pathological feature of ischemic stroke. This study investigated the regulatory role of miR-485-5p in I/R injury. Methods: SH-SY5Y cells were induced with oxygen and glucose deprivation/reoxygenation (OGD/R) to mimic I/R injury in vitro. Cells were transfected with designated constructs (miR-485- 5p mimics, miR-485-5p inhibitor, lentiviral vectors overexpressing Rac1 or their corresponding controls). Cell viability was evaluated using the MTT assay. The concentrations of lactate dehydrogenase, malondialdehyde, and reactive oxygen species were detected to indicate the degree of oxidative stress. Flow cytometry and caspase-3 activity assay were used for apoptosis assessment. Dual-luciferase reporter assay was performed to confirm that Rac family small GTPase 1 (Rac1) was a downstream gene of miR-485-5p. Results: OGD/R resulted in decreased cell viability, elevated oxidative stress, increased apoptosis, and downregulated miR-485-5p expression in SH-SY5Y cells. MiR-485-5p upregulation alleviated I/R injury, evidenced by improved cell viability, decreased oxidative markers, and reduced apoptotic rate. OGD/R increased the levels of Rac1 and neurogenic locus notch homolog protein 2 (Notch2) signaling-related proteins in cells with normal miR-485-5p expression, whereas miR- 485-5p overexpression successfully suppressed OGD/R-induced upregulation of these proteins. Furthermore, the delivery of vectors overexpressing Rac1 in miR-485-5p mimics-transfected cells reversed the protective effect of miR-485-5p in cells with OGD/R-induced injury. Conclusion: This study showed that miR-485-5p protected cells following I/R injury via targeting Rac1/Notch2 signaling suggest that targeted upregulation of miR-485-5p might be a promising therapeutic option for the protection against I/R injury.

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iPLA2β Contributes to ER Stress-Induced Apoptosis during Myocardial Ischemia/Reperfusion Injury

Cells ◽

10.3390/cells10061446 ◽

2021 ◽

Vol 10 (6) ◽

pp. 1446

Author(s):

Tingting Jin ◽

Jun Lin ◽

Yingchao Gong ◽

Xukun Bi ◽

Shasha Hu ◽

...

Keyword(s):

Cell Death ◽

Heart Disease ◽

Myocardial Ischemia ◽

Ischemic Heart Disease ◽

Er Stress ◽

Ischemia Reperfusion ◽

Myocardial Ischemia Reperfusion ◽

Induced Apoptosis

Both calcium-independent phospholipase A2 beta (iPLA2β) and endoplasmic reticulum (ER) stress regulate important pathophysiological processes including inflammation, calcium homeostasis and apoptosis. However, their roles in ischemic heart disease are poorly understood. Here, we show that the expression of iPLA2β is increased during myocardial ischemia/reperfusion (I/R) injury, concomitant with the induction of ER stress and the upregulation of cell death. We further show that the levels of iPLA2β in serum collected from acute myocardial infarction (AMI) patients and in samples collected from both in vivo and in vitro I/R injury models are significantly elevated. Further, iPLA2β knockout mice and siRNA mediated iPLA2β knockdown are employed to evaluate the ER stress and cell apoptosis during I/R injury. Additionally, cell surface protein biotinylation and immunofluorescence assays are used to trace and locate iPLA2β. Our data demonstrate the increase of iPLA2β augments ER stress and enhances cardiomyocyte apoptosis during I/R injury in vitro and in vivo. Inhibition of iPLA2β ameliorates ER stress and decreases cell death. Mechanistically, iPLA2β promotes ER stress and apoptosis by translocating to ER upon myocardial I/R injury. Together, our study suggests iPLA2β contributes to ER stress-induced apoptosis during myocardial I/R injury, which may serve as a potential therapeutic target against ischemic heart disease.

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MiR-22-3p suppresses sepsis-induced acute kidney injury by targeting PTEN

Bioscience Reports ◽

10.1042/bsr20200527 ◽

2020 ◽

Vol 40 (6) ◽

Author(s):

Xudong Wang ◽

Yali Wang ◽

Mingjian Kong ◽

Jianping Yang

Keyword(s):

Acute Kidney Injury ◽

Inflammatory Response ◽

Periodic Acid ◽

Kidney Injury ◽

Luciferase Reporter ◽

Tunel Staining ◽

Tnf Α

Abstract Background: Septic acute kidney injury is considered as a severe and frequent complication that occurs during sepsis. The present study was performed to understand the role of miR-22-3p and its underlying mechanism in sepsis-induced acute kidney injury. Methods: Rats were injected with adenovirus carrying miR-22-3p or miR-NC in the caudal vein before cecal ligation. Meanwhile, HK-2 cells were transfected with the above adenovirus following LPS stimulation. We measured the markers of renal injury (blood urea nitrogen (BUN), serum creatinine (SCR)). Histological changes in kidney tissues were examined by hematoxylin and eosin (H&E), Masson staining, periodic acid Schiff staining and TUNEL staining. The levels of IL-1β, IL-6, TNF-α and NO were determined by ELISA assay. Using TargetScan prediction and luciferase reporter assay, we predicted and validated the association between PTEN and miR-22-3p. Results: Our data showed that miR-22-3p was significantly down-regulated in a rat model of sepsis-induced acute kidney injury, in vivo and LPS-induced sepsis model in HK-2 cells, in vitro. Overexpression of miR-22-3p remarkably suppressed the inflammatory response and apoptosis via down-regulating HMGB1, p-p65, TLR4 and pro-inflammatory factors (IL-1β, IL-6, TNF-α and NO), both in vivo and in vitro. Moreover, PTEN was identified as a target of miR-22-3p. Furthermore, PTEN knockdown augmented, while overexpression reversed the suppressive role of miR-22-3p in LPS-induced inflammatory response. Conclusions: Our results showed that miR-22-3p induced protective role in sepsis-induced acute kidney injury may rely on the repression of PTEN.

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