scholarly journals Maresin conjugates in tissue regeneration-1 suppresses ferroptosis in septic acute kidney injury

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Ji Xiao ◽  
Qian Yang ◽  
Ye’an Zhang ◽  
Haoran Xu ◽  
Yang Ye ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Tissue Regeneration ◽  
Inflammatory Diseases ◽  
Kidney Injury ◽  
Organ Injury ◽  
Related Factor ◽  
Pathophysiological Mechanism ◽  
Regulated Cell Death ◽  
Septic Acute Kidney Injury ◽  
Inflammation Resolution

Abstract Background Ferroptosis is unique among different types of regulated cell death and closely related to organ injury. Whether ferroptosis occurs in sepsis-associated acute kidney injury (SA-AKI) is not clear. Nuclear factor-erythroid-2-related factor 2 (Nrf2) is crucial to the regulation of ferroptosis. We and others have shown that Maresin conjugates in tissue regeneration 1 (MCTR1) or other members of specialized pro-resolving mediators (SPMs) can actively regulate inflammation resolution and protect organs against injury in inflammatory diseases by activating the Nrf2 signaling. The aim of this study was to determine whether ferroptosis occurs in SA-AKI. Furthermore, we investigated the potential role and mechanism of MCTR1 in the regulation of ferroptosis in SA-AKI, which mainly focus on the Nrf2 signaling. Results We demonstrated for the first time that ferroptosis is present in SA-AKI. Moreover, MCTR1 effectively suppressed ferroptosis in SA-AKI. Meanwhile, MCTR1 upregulated the expression of Nrf2 in the kidney of septic mice. Nrf2 inhibitor ML-385 reversed MCTR1-regulated ferroptosis and AKI, implying that Nrf2 is involved in the inhibitory effects of MCTR1 on ferroptosis in SA-AKI. Further, MCTR1 inhibited ferroptosis and elevated the expression of Nrf2 in LPS-induced HK-2 cells. However, Nrf2 siRNA offset the effect of MCTR1 on ferroptosis. Finally, we observed that MCTR1 ameliorates multi-organ injury and improves survival in animal models of sepsis. Conclusions These data demonstrate that MCTR1 suppresses ferroptosis in SA-AKI through the Nrf2 signaling. Our study enriches the pathophysiological mechanism of SA-AKI and provides new therapeutic ideas and potential intervention targets for SA-AKI.

scholarly journals Gasdermin E deficiency attenuates acute kidney injury by inhibiting pyroptosis and inflammation

2021 ◽  
Vol 12 (2) ◽  
Author(s):  
Weiwei Xia ◽  
Yuanyuan Li ◽  
Mengying Wu ◽  
Qianqian Jin ◽  
Qian Wang ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Caspase 3 ◽  
Inflammatory Diseases ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Tubular Epithelial Cells ◽  
Regulated Cell Death ◽  
Deficient Mice

AbstractPyroptosis, one kind of inflammatory regulated cell death, is involved in various inflammatory diseases, including acute kidney injury (AKI). Besides Gasdermin D (GSDMD), GSDME is a newly identified mediator of pyroptosis via the cleavage of caspase-3 generating pyroptotic GSDME-N. Here, we investigated the role of GSDME in renal cellular pyroptosis and AKI pathogenesis employing GSDME-deficient mice and human tubular epithelial cells (TECs) with the interventions of pharmacological and genetic approaches. After cisplatin treatment, GSDME-mediated pyroptosis was induced as shown by the characteristic pyroptotic morphology in TECs, upregulated GSDME-N expression and enhanced release of IL-1β and LDH, and decreased cell viability. Strikingly, silencing GSDME in mice attenuated acute kidney injury and inflammation. The pyroptotic role of GSDME was also verified in human TECs in vitro. Further investigation showed that inhibition of caspase-3 blocked GSDME-N cleavage and attenuated cisplatin-induced pyroptosis and kidney dysfunction. Moreover, deletion of GSDME also protected against kidney injury induced by ischemia-reperfusion. Taken together, the findings from current study demonstrated that caspase-3/GSDME-triggered pyroptosis and inflammation contributes to AKI, providing new insights into the understanding and treatment of this disease.

scholarly journals RIP3 impedes transcription factor EB to suppress autophagic degradation in septic acute kidney injury

2021 ◽  
Vol 12 (6) ◽  
Author(s):  
Ruizhao Li ◽  
Xingchen Zhao ◽  
Shu Zhang ◽  
Wei Dong ◽  
Li Zhang ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Transcription Factor ◽  
Nuclear Translocation ◽  
Kidney Injury ◽  
Septic Acute Kidney Injury ◽  
Transcription Factor Eb ◽  
Autophagic Degradation ◽  
Lps Treatment

AbstractAutophagy is an important renal-protective mechanism in septic acute kidney injury (AKI). Receptor interacting protein kinase 3 (RIP3) has been implicated in the renal tubular injury and renal dysfunction during septic AKI. Here we investigated the role and mechanism of RIP3 on autophagy in septic AKI. We showed an activation of RIP3, accompanied by an accumulation of the autophagosome marker LC3II and the autophagic substrate p62, in the kidneys of lipopolysaccharide (LPS)-induced septic AKI mice and LPS-treated cultured renal proximal tubular epithelial cells (PTECs). The lysosome inhibitor did not further increase the levels of LCII or p62 in LPS-treated PTECs. Moreover, inhibition of RIP3 attenuated the aberrant accumulation of LC3II and p62 under LPS treatment in vivo and in vitro. By utilizing mCherry-GFP-LC3 autophagy reporter mice in vivo and PTECs overexpression mRFP-GFP-LC3 in vitro, we observed that inhibition of RIP3 restored the formation of autolysosomes and eliminated the accumulated autophagosomes under LPS treatment. These results indicated that RIP3 impaired autophagic degradation, contributing to the accumulation of autophagosomes. Mechanistically, the nuclear translocation of transcription factor EB (TFEB), a master regulator of the lysosome and autophagy pathway, was inhibited in LPS-induced mice and LPS-treated PTECs. Inhibition of RIP3 restored the nuclear translocation of TFEB in vivo and in vitro. Co-immunoprecipitation further showed an interaction of RIP3 and TFEB in LPS-treated PTECs. Also, the expression of LAMP1 and cathepsin B, two potential target genes of TFEB involved in lysosome function, were decreased under LPS treatment in vivo and in vitro, and this decrease was rescued by inhibiting RIP3. Finally, overexpression of TFEB restored the autophagic degradation in LPS-treated PTECs. Together, the present study has identified a pivotal role of RIP3 in suppressing autophagic degradation through impeding the TFEB-lysosome pathway in septic AKI, providing potential therapeutic targets for the prevention and treatment of septic AKI.

scholarly journals Risk factors and mortality in patients with sepsis, septic and non septic acute kidney injury in ICU

2019 ◽  
Vol 41 (4) ◽  
pp. 462-471 ◽  
Author(s):  
Kellen Hyde Elias Pinheiro ◽  
Franciana Aguiar Azêdo ◽  
Kelsy Catherina Nema Areco ◽  
Sandra Maria Rodrigues Laranja
Keyword(s):  
Risk Factors ◽  
Acute Kidney Injury ◽  
Kidney Disease ◽  
Kidney Injury ◽  
Mortality Rates ◽  
Icu Patients ◽  
Septic Acute Kidney Injury ◽  
Observational Cohort ◽  
Worse Prognosis

Abstract Acute kidney injury (AKI) has an incidence rate of 5-6% among intensive care unit (ICU) patients and sepsis is the most frequent etiology. Aims: To assess patients in the ICU that developed AKI, AKI on chronic kidney disease (CKD), and/or sepsis, and identify the risk factors and outcomes of these diseases. Methods: A prospective observational cohort quantitative study that included patients who stayed in the ICU > 48 hours and had not been on dialysis previously was carried out. Results: 302 patients were included and divided into: no sepsis and no AKI (nsnAKI), sepsis alone (S), septic AKI (sAKI), non-septic AKI (nsAKI), septic AKI on CKD (sAKI/CKD), and non-septic AKI on CKD (nsAKI/CKD). It was observed that 94% of the patients developed some degree of AKI. Kidney Disease Improving Global Outcomes (KDIGO) stage 3 was predominant in the septic groups (p = 0.018). Nephrologist follow-up in the non-septic patients was only 23% vs. 54% in the septic groups (p < 0.001). Dialysis was performed in 8% of the non-septic and 37% of the septic groups (p < 0.001). Mechanical ventilation (MV) requirement was higher in the septic groups (p < 0.001). Mortality was 38 and 39% in the sAKI and sAKI/CKD groups vs 16% and 0% in the nsAKI and nsAKI/CKD groups, respectively (p < 0.001). Conclusions: Patients with sAKI and sAKI/CKD had worse prognosis than those with nsAKI and nsAKI/CKD. The nephrologist was not contacted in a large number of AKI cases, except for KDIGO stage 3, which directly influenced mortality rates. The urine output was considerably impaired, ICU stay was longer, use of MV and mortality were higher when kidney injury was combined with sepsis.

scholarly journals Effect of hydrocortisone on the 28-day mortality of patients with septic acute kidney injury

Renal Failure ◽  
2019 ◽  
Vol 41 (1) ◽  
pp. 794-799
Author(s):  
Pan Ying ◽  
Chenguang Yang ◽  
Xianlong Wu ◽  
Qiqi Cai ◽  
Wenwei Xin
Keyword(s):  
Acute Kidney Injury ◽  
Kidney Injury ◽  
Septic Acute Kidney Injury

scholarly journals Perioperative Acute Kidney Injury

2020 ◽  
Vol 132 (1) ◽  
pp. 180-204 ◽  
Author(s):  
Sam D. Gumbert ◽  
Felix Kork ◽  
Maisie L. Jackson ◽  
Naveen Vanga ◽  
Semhar J. Ghebremichael ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Kidney Injury ◽  
Fluid Replacement ◽  
Organ Injury ◽  
Surgical Patients ◽  
Creatinine Concentration ◽  
Ongoing Research ◽  
Different Types ◽  
Novel Biomarkers ◽  
Goal Directed Fluid Therapy

Abstract Perioperative organ injury is among the leading causes of morbidity and mortality of surgical patients. Among different types of perioperative organ injury, acute kidney injury occurs particularly frequently and has an exceptionally detrimental effect on surgical outcomes. Currently, acute kidney injury is most commonly diagnosed by assessing increases in serum creatinine concentration or decreased urine output. Recently, novel biomarkers have become a focus of translational research for improving timely detection and prognosis for acute kidney injury. However, specificity and timing of biomarker release continue to present challenges to their integration into existing diagnostic regimens. Despite many clinical trials using various pharmacologic or nonpharmacologic interventions, reliable means to prevent or reverse acute kidney injury are still lacking. Nevertheless, several recent randomized multicenter trials provide new insights into renal replacement strategies, composition of intravenous fluid replacement, goal-directed fluid therapy, or remote ischemic preconditioning in their impact on perioperative acute kidney injury. This review provides an update on the latest progress toward the understanding of disease mechanism, diagnosis, and managing perioperative acute kidney injury, as well as highlights areas of ongoing research efforts for preventing and treating acute kidney injury in surgical patients.

scholarly journals Toll-like Receptor 7 Contributes to Inflammation, Organ Injury, and Mortality in Murine Sepsis

2019 ◽  
Vol 131 (1) ◽  
pp. 105-118 ◽  
Author(s):  
Wenling Jian ◽  
Lili Gu ◽  
Brittney Williams ◽  
Yan Feng ◽  
Wei Chao ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Immune Responses ◽  
Knockout Mice ◽  
Cecal Ligation ◽  
Kidney Injury ◽  
Innate Immune ◽  
Organ Injury ◽  
Innate Immune Responses ◽  
Toll Like Receptor ◽  
Wild Type

Abstract Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New Background Sepsis remains a critical illness with high mortality. The authors have recently reported that mouse plasma RNA concentrations are markedly increased during sepsis and closely associated with its severity. Toll-like receptor 7, originally identified as the sensor for single-stranded RNA virus, also mediates host extracellular RNA-induced innate immune responses in vitro and in vivo. Here, the authors hypothesize that innate immune signaling via Toll-like receptor 7 contributes to inflammatory response, organ injury, and mortality during polymicrobial sepsis. Methods Sepsis was created by (1) cecal ligation and puncture or (2) stool slurry peritoneal injection. Wild-type and Toll-like receptor 7 knockout mice, both in C57BL/6J background, were used. The following endpoints were measured: mortality, acute kidney injury biomarkers, plasma and peritoneal cytokines, blood bacterial loading, peritoneal leukocyte counts, and neutrophil phagocytic function. Results The 11-day overall mortality was 81% in wild-type mice and 48% in Toll-like receptor 7 knockout mice after cecal ligation and puncture (N = 27 per group, P = 0.0031). Compared with wild-type septic mice, Toll-like receptor 7 knockout septic mice also had lower sepsis severity, attenuated plasma cytokine storm (wild-type vs. Toll-like receptor 7 knockout, interleukin-6: 43.2 [24.5, 162.7] vs. 4.4 [3.1, 12.0] ng/ml, P = 0.003) and peritoneal inflammation, alleviated acute kidney injury (wild-type vs. Toll-like receptor 7 knockout, neutrophil gelatinase-associated lipocalin: 307 ± 184 vs.139 ± 41-fold, P = 0.0364; kidney injury molecule-1: 40 [16, 49] vs.13 [4, 223]-fold, P = 0.0704), lower bacterial loading, and enhanced leukocyte peritoneal recruitment and phagocytic activities at 24 h. Moreover, stool slurry from wild-type and Toll-like receptor 7 knockout mice resulted in similar level of sepsis severity, peritoneal cytokines, and leukocyte recruitment in wild-type animals after peritoneal injection. Conclusions Toll-like receptor 7 plays an important role in the pathogenesis of polymicrobial sepsis by mediating host innate immune responses and contributes to acute kidney injury and mortality.

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