Blue light reduces organ injury from ischemia and reperfusion

Evidence suggests that light and circadian rhythms profoundly influence the physiologic capacity with which an organism responds to stress. However, the ramifications of light spectrum on the course of critical illness remain to be determined. Here, we show that acute exposure to bright blue spectrum light reduces organ injury by comparison with bright red spectrum or ambient white fluorescent light in two murine models of sterile insult: warm liver ischemia/reperfusion (I/R) and unilateral renal I/R. Exposure to bright blue light before I/R reduced hepatocellular injury and necrosis and reduced acute kidney injury and necrosis. In both models, blue light reduced neutrophil influx, as evidenced by reduced myeloperoxidase (MPO) within each organ, and reduced the release of high-mobility group box 1 (HMGB1), a neutrophil chemotactant and key mediator in the pathogenesis of I/R injury. The protective mechanism appeared to involve an optic pathway and was mediated, in part, by a sympathetic (β3 adrenergic) pathway that functioned independent of significant alterations in melatonin or corticosterone concentrations to regulate neutrophil recruitment. These data suggest that modifying the spectrum of light may offer therapeutic utility in sterile forms of cellular injury.

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Endothelial STAT3 Modulates Protective Mechanisms in a Mouse Ischemia-Reperfusion Model of Acute Kidney Injury

Journal of Immunology Research ◽

10.1155/2017/4609502 ◽

2017 ◽

Vol 2017 ◽

pp. 1-9 ◽

Cited By ~ 5

Author(s):

Shataakshi Dube ◽

Tejasvi Matam ◽

Jessica Yen ◽

Henry E. Mang ◽

Pierre C. Dagher ◽

...

Keyword(s):

Acute Kidney Injury ◽

Ischemia Reperfusion Injury ◽

Leukocyte Adhesion ◽

Ischemia Reperfusion ◽

Kidney Injury ◽

Organ Injury ◽

Mrna Levels ◽

Kidney Dysfunction ◽

Stat3 Signaling ◽

Proximal Tubular

STAT3 is a transcriptional regulator that plays an important role in coordinating inflammation and immunity. In addition, there is a growing appreciation of the role STAT3 signaling plays in response to organ injury following diverse insults. Acute kidney injury (AKI) from ischemia-reperfusion injury is a common clinical entity with devastating consequences, and the recognition that endothelial alterations contribute to kidney dysfunction in this setting is of growing interest. Consequently, we used a mouse with a genetic deletion of Stat3 restricted to the endothelium to examine the role of STAT3 signaling in the pathophysiology of ischemic AKI. In a mouse model of ischemic AKI, the loss of endothelial STAT3 signaling significantly exacerbated kidney dysfunction, morphologic injury, and proximal tubular oxidative stress. The increased severity of ischemic AKI was associated with more robust endothelial-leukocyte adhesion and increased tissue accumulation of F4/80+ macrophages. Moreover, important proximal tubular adaptive mechanisms to injury were diminished in association with decreased tissue mRNA levels of the epithelial cell survival cytokine IL-22. In aggregate, these findings suggest that the endothelial STAT3 signaling plays an important role in limiting kidney dysfunction in ischemic AKI and that selective pharmacologic activation of endothelial STAT3 signaling could serve as a potential therapeutic target.

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Peroxiredoxin-6 protects against mitochondrial dysfunction and liver injury during ischemia-reperfusion in mice

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.90583.2008 ◽

2009 ◽

Vol 296 (2) ◽

pp. G266-G274 ◽

Cited By ~ 94

Author(s):

Thorsten Eismann ◽

Nadine Huber ◽

Thomas Shin ◽

Satoshi Kuboki ◽

Elizabeth Galloway ◽

...

Keyword(s):

Mitochondrial Dysfunction ◽

Mitochondrial Function ◽

Knockout Mice ◽

Ischemia Reperfusion ◽

Protective Mechanism ◽

Wild Type ◽

Hepatocellular Injury ◽

Hepatic Ischemia ◽

Altered Expression ◽

Peroxiredoxin 6

Hepatic ischemia-reperfusion (I/R) injury is an important complication of liver surgery and transplantation. Mitochondrial function is central to this injury. To examine alterations in mitochondrial function during I/R, we assessed the mitochondrial proteome in C57Bl/6 mice. Proteomic analysis of liver mitochondria revealed 234 proteins with significantly altered expression after I/R. From these, 13 proteins with the greatest expression differences were identified. One of these proteins, peroxiredoxin-6 (Prdx6), has never before been described in mitochondria. In hepatocytes from sham-operated mice, Prdx6 expression was found exclusively in the cytoplasm. After ischemia or I/R, Prdx6 expression disappeared from the cytoplasm and appeared in the mitochondria, suggesting mitochondrial trafficking. To explore the functional role of Prdx6 in hepatic I/R injury, wild-type and Prdx6-knockout mice were subjected to I/R injury. Prdx6-knockout mice had significantly more hepatocellular injury compared with wild-type mice. Interestingly, the increased injury in Prdx6-knockout mice occurred despite reduced inflammation and was associated with increased mitochondrial generation of H2O2 and dysfunction. The mitochondrial dysfunction appeared to be related to complex I of the electron transport chain. These data suggest that hepatocyte Prdx6 traffics to the mitochondria during I/R to limit mitochondrial dysfunction as a protective mechanism against hepatocellular injury.

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Transcriptional trajectories of human kidney disease progression

10.1101/342972 ◽

2018 ◽

Author(s):

Pietro E Cippà ◽

Bo Sun ◽

Jing Liu ◽

Liang Chen ◽

Maarten Naesens ◽

...

Keyword(s):

Disease Progression ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Transcriptional Response ◽

Kidney Injury ◽

Human Kidney ◽

Organ Injury ◽

Machine Learning Techniques ◽

Integrated Analysis ◽

Clinical Conditions

AbstractOur molecular understanding of clinical conditions progressing from acute organ injury to irreversible dysfunction is limited. We used renal transplantation as a model to characterize the transcriptional response along the transition from acute kidney injury to allograft fibrosis in humans. The integrated analysis of 163 transcriptomes with machine learning techniques identified shared and divergent transcriptional trajectories determining distinct clinical outcomes in a heterogeneous population. The molecular map of renal responses to injury was validated in a mouse ischemia-reperfusion injury model and highlighted early markers of disease progression. This generally applicable approach opens the way for an unbiased analysis of progressive diseases.

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Inflammatory Mechanisms of Organ Crosstalk during Ischemic Acute Kidney Injury

International Journal of Nephrology ◽

10.4061/2012/505197 ◽

2012 ◽

Vol 2012 ◽

pp. 1-8 ◽

Cited By ~ 42

Author(s):

Laura E. White ◽

Heitham T. Hassoun

Keyword(s):

Acute Kidney Injury ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Adaptive Immune Response ◽

Kidney Injury ◽

Cellular Adhesion ◽

Organ Injury ◽

Recent Experimental Data ◽

Organ Crosstalk ◽

Formidable Challenge

Acute kidney injury (AKI) is a common complication during inpatient hospitalization, and clinical outcomes remain poor despite advancements in renal replacement therapy. AKI in the setting of multiple organ failure (MOF) remains a formidable challenge to clinicians and incurs an unacceptably high mortality rate. Kidney ischemia-reperfusion injury (IRI) incites a proinflammatory cascade and releases cellular and soluble mediators with systemic implications for remote organ injury. Evidence from preclinical models cites mechanisms of organ crosstalk during ischemic AKI including the expression of cellular adhesion molecules, lymphocyte trafficking, release of proinflammatory cytokines and chemokines, and modification of the host innate and adaptive immune response systems. In this paper, the influence of kidney IRI on systemic inflammation and distant organ injury will be examined. Recent experimental data and evolving concepts of organ crosstalk during ischemic AKI will also be discussed in detail.

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Inhibition of 15-PGDH prevents ischemic renal injury by the PGE2/EP4 signaling pathway mediating vasodilation, increased renal blood flow, and increased adenosine/A2A receptors

AJP Renal Physiology ◽

10.1152/ajprenal.00103.2020 ◽

2020 ◽

Vol 319 (6) ◽

pp. F1054-F1066

Author(s):

Hye Jung Kim ◽

Sun-Hee Kim ◽

Minjung Kim ◽

HyungJoo Baik ◽

Seok Ju Park ◽

...

Keyword(s):

Blood Flow ◽

Renal Blood Flow ◽

Renal Injury ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

High Mobility ◽

Kidney Injury ◽

Clinical Problem ◽

Protective Effects

In the present study, we demonstrated the marked activity of SW033291, an inhibitor of 15-hydoxyprostaglandin dehydrogenase (15-PGDH), in preventing acute kidney injury (AKI) in a murine model of ischemia-reperfusion injury. AKI due to ischemic injury represents a significant clinical problem. PGE2 is vasodilatory in the kidney, but it is rapidly degraded in vivo due to catabolism by 15-PGDH. We investigated the potential of SW033291, a potent and specific 15-PGDH inhibitor, as prophylactic treatment for ischemic AKI. Prophylactic administration of SW033291 significantly increased renal tissue PGE2 levels and increased post-AKI renal blood flow and renal arteriole area. In parallel, prophylactic SW033291 decreased post-AKI renal morphology injury scores and tubular apoptosis and markedly reduced biomarkers of renal injury that included blood urea nitrogen, creatinine, neutrophil gelatinase-associated lipocalin, and kidney injury molecule-1. Prophylactic SW033291 also reduced post-AKI induction of proinflammatory cytokines, high-mobility group box 1, and malondialdehyde. Protective effects of SW033291 were mediated by PGE2 signaling, as they could be blocked by pharmacological inhibition of PGE2 synthesis. Consistent with activation of PGE2 signaling, SW033291 induced renal levels of both EP4 receptors and cAMP, along with other vasodilatory effectors, including AMP, adenosine, and the adenosine A2A receptor. The protective effects of SW0333291 could largely be achieved with a single prophylactic dose of the drug. Inhibition of 15-PGDH may thus represent a novel strategy for prophylaxis of ischemic AKI in multiple clinical settings, including renal transplantation and cardiovascular surgery.

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TNFR1-dependent pulmonary apoptosis during ischemic acute kidney injury

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00301.2011 ◽

2012 ◽

Vol 303 (5) ◽

pp. L449-L459 ◽

Cited By ~ 17

Author(s):

Laura E. White ◽

Rachel J. Santora ◽

Yan Cui ◽

Frederick A. Moore ◽

Heitham T. Hassoun

Keyword(s):

Acute Kidney Injury ◽

Complex I ◽

Time Course ◽

Ischemia Reperfusion ◽

Kidney Injury ◽

Organ Injury ◽

Yield Potential ◽

Caspase 8 ◽

Complex Ii ◽

Tnf Α

Despite advancements in renal replacement therapy, the mortality rate for acute kidney injury (AKI) remains unacceptably high, likely due to remote organ injury. Kidney ischemia-reperfusion injury (IRI) activates cellular and soluble mediators that incite a distinct pulmonary proinflammatory and proapoptotic response. Tumor necrosis factor receptor 1 (TNFR1) has been identified as a prominent death receptor activated in the lungs during ischemic AKI. We hypothesized that circulating TNF-α released from the postischemic kidney induces TNFR1-mediated pulmonary apoptosis, and we aimed to elucidate molecular pathways to programmed cell death. Using an established murine model of kidney IRI, we characterized the time course for increased circulatory and pulmonary TNF-α levels and measured concurrent upregulation of pulmonary TNFR1 expression. We then identified TNFR1-dependent pulmonary apoptosis after ischemic AKI using TNFR1−/− mice. Subsequent TNF-α signaling disruption with Etanercept implicated circulatory TNF-α as a key soluble mediator of pulmonary apoptosis and lung microvascular barrier dysfunction during ischemic AKI. We further elucidated pathways of TNFR1-mediated apoptosis with NF-κB (Complex I) and caspase-8 (Complex II) expression and discovered that TNFR1 proapoptotic signaling induces NF-κB activation. Additionally, inhibition of NF-κB (Complex I) resulted in a proapoptotic phenotype, lung barrier leak, and altered cellular flice inhibitory protein signaling independent of caspase-8 (Complex II) activation. Ischemic AKI activates soluble TNF-α and induces TNFR1-dependent pulmonary apoptosis through augmentation of the prosurvival and proapoptotic TNFR1 signaling pathway. Kidney-lung crosstalk after ischemic AKI represents a complex pathological process, yet focusing on specific biological pathways may yield potential future therapeutic targets.

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The Role of TRPC6 in Renal Ischemia/Reperfusion and Cellular Hypoxia/Reoxygenation Injuries

Frontiers in Molecular Biosciences ◽

10.3389/fmolb.2021.698975 ◽

2021 ◽

Vol 8 ◽

Author(s):

Xin Hou ◽

Mengjun Huang ◽

Xixi Zeng ◽

Yanhong Zhang ◽

Anbang Sun ◽

...

Keyword(s):

Transient Receptor Potential ◽

Ischemia Reperfusion ◽

Kidney Injury ◽

Receptor Potential ◽

Renal Ischemia ◽

Clinical Event ◽

Renal Diseases ◽

Protective Mechanism ◽

Cellular Mechanisms

Renal ischemia/reperfusion (I/R), a major cause of acute kidney injury (AKI), is a serious clinical event in patients during post-renal transplantation. I/R is associated with renal dysfunction and tubular apoptosis, and calcium (Ca2+) overload has been reported to be a crucial factor on tubular apoptosis in I/R injury (IRI). The canonical transient receptor potential channel 6 (TRPC6), a type of non-selective Ca2+ channel, is involved in many renal diseases. Our earlier study identified that TRPC6-mediated Ca2+ influx plays a novel role in suppressing cytoprotective autophagy triggered by oxidative stress in primary tubular epithelial cells (TECs). This study explored the potential beneficial impact of TRPC6 knockout (TRPC6−/−) and the relevant cellular mechanisms against I/R-induced AKI in mice. Measuring changes of renal function, apoptotic index, and autophagy in mouse kidneys that suffered 24 h reperfusion after 40 min ischemia and working in vitro with TECs that suffered 24 h reoxygenation after 24 h hypoxia, we found that 1) IRI tissues had increased TRPC6 expression and TRPC6 knockout significantly ameliorated renal damage induced by IRI; 2) TRPC6 knockout enhanced the level of autophagy and alleviated the depolarization of mitochondrial membrane potential (ψm, MMP) and apoptotic changes upon IRI; and 3) IRI tissues had increased p-AKT and p-ERK1/2 expressions, while TRPC6 knockout could markedly reduce the phosphorylation of AKT and ERK1/2. These discoveries suggest that, by reducing Ca2+ overload, the underlying protective mechanism of TRPC6−/− may be involved in down-regulation of PI3K/AKT and ERK signaling, which is likely to provide a new avenue for future AKI therapies.

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Effects of dexmedetomidine on renal microcirculation in ischemia/reperfusion-induced acute kidney injury in rats

Scientific Reports ◽

10.1038/s41598-021-81288-3 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Szu-Jen Yang ◽

◽

Chia-Ning Fan ◽

Ming-Jiuh Wang ◽

Shou-Zen Fan ◽

...

Keyword(s):

Acute Kidney Injury ◽

Repeated Measures ◽

Ischemia Reperfusion ◽

Kidney Injury ◽

Vessel Density ◽

Organ Injury ◽

Small Vessel ◽

Tissue Oxygen Saturation ◽

Flow Index ◽

Renal Microcirculation

AbstractMicrocirculatory dysfunction plays a crucial role in renal ischemia/reperfusion (IR)-induced injury. Dexmedetomidine was reported to ameliorate IR-induced acute kidney injury. This study investigated the effects of dexmedetomidine on renal microcirculation after IR-induced acute kidney injury in rats. In total, 50 rats were randomly allocated to the following five groups (10 in each group): Sham, Control‒IR, Dex (dexmedetomidine) ‒Sham, Dex‒IR, and IR‒Dex group. The microcirculation parameters included total small vessel density, perfused small vessel density (PSVD), proportion of perfused small vessels, microvascular flow index, and tissue oxygen saturation (StO2) were recorded. The repeated measures analysis showed that PSVD on renal surface was higher in the Dex‒IR group than in the Control‒IR group (3.5 mm/mm2, 95% confidence interval [CI] 0.6 to 6.4 mm/mm2, P = 0.01). At 240 min, StO2 on renal surface was lower in the Control‒IR group than in the Sham group (– 7%, 95% CI − 13 to − 1%, P = 0.021), but StO2 did not differ significantly among the Sham, Dex‒IR, and IR‒Dex groups. Our results showed that pretreatment with dexmedetomidine improved renal microcirculation in rats with IR-induced acute kidney injury. However, the adverse effects of low mean arterial pressure and heart rate might offset the protective effect of dexmedetomidine on organ injury.

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