Dysfunction In Acute Kidney Injury Research Articles

#1225 Lactate aggravates mitochondrial dysfunction via ALDH2 lactylation in acute kidney injury

Abstract Background and Aims Elevated lactate levels have been recognized as an independent risk factor in acute kidney injury (AKI) contributed by mitochondrial dysfunction. We previously proved the crucial role of acetaldehyde dehydrogenase 2 (ALDH2) in AKI but not focused on the lactate and lactylation of ALDH2. Method We first established a maleic acid (MA) induced AKI model (MA-AKI) in C57BL/6J mice, administrating 2-DG i.p. (a glycolysis inhibitor) or oxamate (a lactate dehydrogenase A inhibitor) to suppress the lactate production. We measured the renal function, mitochondrial function, and lactate in serum and urine, then evaluated the ALDH2 lactylation by co-immunoprecipitation assays, and identified the specific lactation site by mass spectrum. The role of ALDH2 lactylation was explored through point mutation in HEK293 cells. Furthermore, an ALDH2 lactylation eraser was identified, and its function was elucidated in mice and HK-2 cells. Results The elevated lactate in the kidney, serum, and urine showed a significant positive correlation to the serum creatinine (Scr, R2 = 0.83, P < 0.0001) in MA-induced mice. Both 2-DG and oxamate partly abolished the Scr increasing and the proximal tubular histopathological injuries. Increased pan-lactylation in AKI mice was effectively inhibited by oxamate, parallel with increased ALDH2 lactylation in MA-stimulated HK-2 cells. Mass spectrometry identified a single lactylate lysine residue in ALDH2 (K52). The introduction of a point mutation (K52 to R) in ALDH2, mimicking the delactylated state, led to partial recovery of ALDH2 activity (1.11 ± 0.07 vs. 0.68 ± 0.15, P = 0.0029) and mitochondrial function in MA-stimulated HK-2 cells. Additionally, sirt3 was identified as an ALDH2 lactylation eraser, and Honokiol (a sirt3 activator) demonstrated enhanced renal function and mitigation of mitochondrial dysfunction in both MA-induced mice and HK-2 cells. Conclusion Lactate played a crucial role in mitochondrial dysfunction in AKI partly via induction of ALDH2 lactylation, which shed light on the potential target for the therapy.

Prognostic impact and predictors of persistent renal dysfunction in acute kidney injury after percutaneous coronary intervention for acute myocardial infarction.

This study aimed to evaluate the prognostic impact and predictors of persistent renal dysfunction in acute kidney injury (AKI) after an emergency percutaneous coronary intervention (PCI) for acute myocardial infarction (AMI). A total of 877 patients who underwent emergency PCI for AMI were examined. AKI was defined as serum creatinine (SCr) ≥ 0.3mg/dL or ≥ 50% from baseline within 48h after PCI. Persistent AKI was defined as residual impairment of SCr ≥ 0.3mg/dL or ≥ 50% from baseline 1month after the procedure. The primary outcome was the composite endpoints of death, myocardial infarction, hospitalization for heart failure, stroke, and dialysis. AKI and persistent AKI were observed in 82 (9.4%) and 25 (2.9%) patients, respectively. Multivariate Cox proportional hazards analysis demonstrated that persistent AKI, but not transient AKI, was an independent predictor of primary outcome (hazard ratio, 4.99; 95% confidence interval, 2.30-10.8; P < 0.001). Age > 75years, left ventricular ejection fraction < 40%, a high maximum creatinine phosphokinase MB level, and bleeding after PCI were independently associated with persistent AKI. Persistent AKI was independently associated with worse clinical outcomes in patients who underwent emergency PCI for AMI. Advanced age, poor cardiac function, large myocardial necrosis, and bleeding were predictors of persistent AKI.

Phloretin as an add-on therapy to losartan attenuates diabetes-induced AKI in rats: A potential therapeutic approach targeting TLR4-induced inflammation

AimTargeting Toll-like receptor 4 (TLR4) and Angiotensin II type 1 receptor (AT1R) could provide renoprotection during acute kidney injury (AKI) mainly by regulating inflammation, oxidative stress, mitochondrial dysfunction, and apoptosis. Phloretin (TLR4 inhibitor) as an add-on therapy to losartan (AT1R inhibitor) could provide more therapeutic benefits against AKI under diabetic condition. We aimed to study the effect of phloretin as an add-on therapy to losartan against AKI under diabetic condition. Main methodsTo mimic diabetic AKI condition, bilateral ischemia-reperfusion injury (BIRI) was done in diabetic male Wistar rats, and sodium azide treatment was given to high glucose NRK52E cells to mimic hypoxia-reperfusion injury. In diabetic rats, phloretin (50 mg/kg/per os (p.o.)) and losartan (10 mg/kg/p.o.) treatment was given for 4 days and 1 h prior to surgery while in NRK52E cells, both drugs (phloretin 50 μM and losartan 10 μM) were given 24 h prior to the hypoxia condition. The in vivo and in vitro samples were further used for different experiments. Key findingsTreatment with phloretin and losartan decreased diabetic and AKI biomarkers such as plasma creatinine, blood urea nitrogen (BUN), and kidney injury molecular 1 (KIM1). Moreover, a combination of phloretin and losartan significantly preserved ΔΨm and kidney morphology potentially by inhibiting TLR4-associated inflammation and AT1R-associated mitochondrial dysfunction, thereby oxidative stress. SignificanceCombination therapy of phloretin and losartan was more effective than monotherapies. Both drugs target TLR4/MyD88/NF-κB pathway and reduce inflammation and mitochondrial dysfunction in AKI under diabetic condition.

Use of peroxiredoxin 6 to prevent liver dysfunction in acute kidney injury

Acute kidney injury causes deterioration of liver function, that is a confounding factor affecting treatment outcomes. In this work, renal ischemia reperfusion injury was used as a model. Taking into account that hyperproduction of reactive oxygen species is the major risk factor for kidney damage, the exogenous antioxidant enzyme peroxiredoxin 6, able to neutralize reactive oxygen species, has been used to prevent liver damage when kidneys are damaged. Kidney injury was initiated by a 45-minute ischemia simultaneously with a left-sided donor nephrectomy without manipulations of the liver. Peroxiredoxin 6 was administered intravenously 15 minutes before ischemia. The functional state of the liver was assessed after 2, 5 and 24 hours of reperfusion using histological and biochemical analysis. The signs of liver damage were detected in the best possible way after 5 hours of kidney reperfusion. It was found that peroxiredoxin 6 helps reduce the severity of the vascular reaction and leukocyte infiltration in the liver; lower the level of dystrophy and apoptosis of hepatocytes; keep the concentration of TBA-reactive products even and stabilize the level of cytokines, IL-6 and IL-10, in the liver tissue, as well as normalize the activity of intracellular transferases in the blood at the onset of reperfusion. The protective effect of peroxiredoxin 6 is associated primarily with its antioxidant properties, due to which hyperproduction of reactive oxygen species can be neutralized in the early phase of kidney reperfusion, but the signal-regulatory function of the protein can also contribute to a protective role peroxiredoxin 6.

Use of Peroxiredoxin 6 to Prevent Liver Dysfunction in Acute Kidney Injury

Use of Peroxiredoxin 6 to Prevent Liver Dysfunction in Acute Kidney Injury

Metabolic impact of genetic and chemical ADP/ATP carrier inhibition in renal proximal tubule epithelial cells

Mitochondrial dysfunction is pivotal in drug-induced acute kidney injury (AKI), but the underlying mechanisms remain largely unknown. Transport proteins embedded in the mitochondrial inner membrane form a significant class of potential drug off-targets. So far, most transporter-drug interactions have been reported for the mitochondrial ADP/ATP carrier (AAC). Since it remains unknown to what extent AAC contributes to drug-induced mitochondrial dysfunction in AKI, we here aimed to better understand the functional role of AAC in the energy metabolism of human renal proximal tubular cells. To this end, CRISPR/Cas9 technology was applied to generate AAC3−/− human conditionally immortalized renal proximal tubule epithelial cells. This AAC3−/− cell model was characterized with respect to mitochondrial function and morphology. To explore whether this model could provide first insights into (mitochondrial) adverse drug effects with suspicion towards AAC-mediated mechanisms, wild-type and knockout cells were exposed to established AAC inhibitors, after which cellular metabolic activity and mitochondrial respiratory capacity were measured. Two AAC3−/− clones showed a significant reduction in ADP import and ATP export rates and mitochondrial mass, without influencing overall morphology. AAC3−/− clones exhibited reduced ATP production, oxygen consumption rates and metabolic spare capacity was particularly affected, mainly in conditions with galactose as carbon source. Chemical AAC inhibition was stronger compared to genetic inhibition in AAC3−/−, suggesting functional compensation by remaining AAC isoforms in our knockout model. In conclusion, our results indicate that ciPTEC-OAT1 cells have a predominantly oxidative phenotype that was not additionally activated by switching energy source. Genetic inhibition of AAC3 particularly impacted mitochondrial spare capacity, without affecting mitochondrial morphology, suggesting an important role for AAC in maintaining the metabolic spare respiration.

Aldehyde dehydrogenase 2 alleviates mitochondrial dysfunction by promoting PGC-1α-mediated biogenesis in acute kidney injury

Renal tubular epithelial cells are one of the high energy-consuming cell types, which mainly depend on mitochondrial energy supply. Aldehyde dehydrogenase 2 (ALDH2) is a key enzyme that is involved in alcohol metabolism and mitochondrial oxidative ATP production; however, its function in mitochondrial homoeostasis in acute kidney injury (AKI) is unclear. Here, we found that ALDH2 expression was predominantly decreased in cisplatin or maleic acid (MA) models both in vivo and in vitro. ALDH2 knockout (KO) mice exhibited exacerbated kidney impairment and apoptosis of tubular epithelial cells after cisplatin injection. In contrast, ALDH2 activation alleviated AKI and tubular cell apoptosis in both cisplatin- and MA-induced models. RNA sequencing revealed that the oxidative phosphorylation pathway was positively enriched in the renal tissues after Alda-1 pre-treatment in MA-induced mice. ALDH2 activation restored mitochondrial structure, mitochondrial membrane potential, and respiration rate, but downregulated glycolysis in MA-induced mice and human renal proximal tubular epithelial (HK-2) cells. Mechanistically, co-immunoprecipitation assays revealed that ALDH2 interacts with peroxisomal proliferator-γ coactivator-1α (PGC-1α), a master regulator of mitochondrial biogenesis, and advanced its nuclear translocation. Subsequently, PGC-1α knockdown almost abolished the improvement of ALDH2 activation on MA-induced tubular epithelial cells damage. Thus, our study revealed that ALDH2 activation alleviated mitochondrial dysfunction in AKI by enhancing PGC-1α-mediated mitochondrial biogenesis. Hence, ALDH2 may act as a potential therapeutic target to prevent AKI progression.

Notoginsenoside Fc ameliorates renal tubular injury and mitochondrial damage in acetaminophen-induced acute kidney injury partly by regulating SIRT3/SOD2 pathway.

Mitochondria dysfunction is one of the primary causes of tubular injury in acute kidney injury (AKI). Notoginsenoside Fc (Fc), a new saponin isolated from Panax notoginseng, exhibited numerous pharmacological actions. However, the beneficial effects of Fc on renal tubular impairment and mitochondrial dysfunction in AKI have not been fully studied. In this study, we established acetaminophen (APAP)-induced AKI model in mice to examine the therapeutic impacts of Fc on AKI. Our results showed that Fc could decrease the levels of the serum creatinine (Scr), blood urea nitrogen (BUN) and Cystatin C in mice with AKI. Fc also ameliorated renal histopathology, renal tubular cells apoptosis and restored expression of apoptosis-related proteins such as Bax, Bcl-2 and caspase3 (C-caspase3). Additionally, Fc increased the protein expression of SIRT3 and SOD2 in kidneys from mice with AKI. In vitro studies further showed Fc reduced the apoptosis of HK-2 cells exposure to APAP, attenuated the loss of mitochondrial membrane potential and decreased the formation of mitochondrial superoxide. Fc also partly restored the protein expression of Bax, Bcl-2, C-Caspase3, SIRT3, and SOD2 in HK-2 cells exposure to APAP. In summary, Fc might reduce renal tubular injury and mitochondrial dysfunction in AKI partly through the regulation of SIRT3/SOD2 pathway.

PS-B08-6: ROLE OF THE HMGB-1/RAGE AXIS AND MINERALOCORTICOID RECEPTOR IN THE PATHOGENESIS OF ACUTE KIDNEY INJURY

Background: Endothelial dysfunction plays a central role in the pathogenesis of cardio-renal syndrome. High mobility group box-1 (HMGB-1) is a protein with various roles in different cellular compartments, and indirectly regulates the activity of transcription and DNA repair in the nucleus. On the other hand, during tissue damage, it is released into the extracellular environment as damage-associated molecular patterns (DAMPs). HMGB-1 is elevated in the pathogenesis of acute kidney injury (AKI) and be involved in endothelial dysfunction through binding to toll like receptor (TLR) and receptor for advanced glycation end products (RAGE). In addition, we recently demonstrated that RAGE-mediated Rac1 activated mineralocorticoid receptor (MR) and subsequently resulted in podocytes damage. In the present study, we hypothesized that crosstalk between HMGB-1/ RAGE and Rac1-MR pathways could contribute to endothelial dysfunction in AKI. Methods: In the present study, we performed a renal ischemia-reperfusion model (I/R group) on C57BL/6J mice to evaluate the expression of Rac1-MR pathway and organ damage. In addition, the I/R group was pretreated with MR blocker (esaxerenone) and evaluated in the same way. In vitro study, we investigated whether HMGB-1 could activate Rac1-MR axis and thus induce endothelial injury in cultured human umbilical vein endothelial cells (HUVECs) by assessing expression levels of genes for MCP-1 and NF-κB with or without administration of RAGE aptamer or MR blocker. Results: In the I/R group, MR activation assessed by translocation into the nucleus and enhanced RAGE expression were observed along with HMGB-1 and RAGE elevation, and pretreatment with MR blocker suppressed the elevation of serum creatinine levels as well as tubular necrosis. Further, the loss of peritubular capillaries observed in I/R kidney was markedly suppressed by MR blocker. In vitro study, HMGB-1 supplementation significantly increased RAGE expression, GTP-bound Rac1 and enhanced MR translocation into the nucleus in HUVECs as well. We also found that HMGB-1 upregulated MCP-1 and NF-κB, all of which were significantly blocked by pretreatment of RAGE aptamer and MR blocker. Conclusion: These results suggest that there may be a close relationship between HMGB-1/ RAGE axis and Rac1/ MR activation, thus contributing endothelial injury. Using RAGE aptamer or MR blocker could be novel therapeutic strategies against endothelial dysfunction in patients with AKI.

Regulator of calcineurin 1 deletion attenuates mitochondrial dysfunction and apoptosis in acute kidney injury through JNK/Mff signaling pathway

Ischemia-reperfusion (I/R) induced acute kidney injury (AKI), characterized by excessive mitochondrial damage and cell apoptosis, remains a clinical challenge. Recent studies suggest that regulator of calcineurin 1 (RCAN1) regulates mitochondrial function in different cell types, but the underlying mechanisms require further investigation. Herein, we aim to explore whether RCAN1 involves in mitochondrial dysfunction in AKI and the exact mechanism. In present study, AKI was induced by I/R and cisplatin in RCAN1flox/flox mice and mice with renal tubular epithelial cells (TECs)-specific deletion of RCAN1. The role of RCAN1 in hypoxia-reoxygenation (HR) and cisplatin-induced injury in human renal proximal tubule epithelial cell line HK-2 was also examined by overexpression and knockdown of RCAN1. Mitochondrial function was assessed by transmission electron microscopy, JC-1 staining, MitoSOX staining, ATP production, mitochondrial fission and mitophagy. Apoptosis was detected by TUNEL assay, Annexin V-FITC staining and Western blotting analysis of apoptosis-related proteins. It was found that protein expression of RCAN1 was markedly upregulated in I/R- or cisplatin-induced AKI mouse models, as well as in HR models in HK-2 cells. RCAN1 deficiency significantly reduced kidney damage, mitochondrial dysfunction, and cell apoptosis, whereas RCAN1 overexpression led to the opposite phenotypes. Our in-depth mechanistic exploration demonstrated that RCAN1 increases the phosphorylation of mitochondrial fission factor (Mff) by binding to downstream c-Jun N-terminal kinase (JNK), then promotes dynamin related protein 1 (Drp1) migration to mitochondria, ultimately leads to excessive mitochondrial fission of renal TECs. In conclusion, our study suggests that RCAN1 could induce mitochondrial dysfunction and apoptosis by activating the downstream JNK/Mff signaling pathway. RCAN1 may be a potential therapeutic target for conferring protection against I/R- or cisplatin-AKI.

NAD+ ameliorates endotoxin-induced acute kidney injury in a sirtuin1-dependent manner via GSK-3β/Nrf2 signalling pathway.

Acute kidney injury (AKI) is a substantial worldwide public health concern with no specific and effective therapies in clinic. NAD+ is a pivotal determinant of cellular energy metabolism involved in the progression of AKI; however, its mechanism in kidney injury remains poorly understood. Sirtuin 1 (SIRT1) is an NAD+‐dependent deacetylase associated with renal protection and acute stress resistance. In this study, we have investigated the role of NAD+ in AKI and the potential mechanism(s) involved in its renoprotective effect. NAD+ was notably decreased and negatively correlated with kidney dysfunction in AKI, restoring NAD+ with NMN significantly ameliorates LPS‐induced oxidative stress and apoptosis and attenuates renal damage. We also found that the protection of NAD+ is associated with SIRT1 expressions and performs in a SIRT1‐dependent manner. Inhibition of SIRT1 blunted the protective effect of NAD+ and up‐regulated the activity of glycogen synthase kinase‐3β (GSK‐3β) that was concomitant with mitigated Nrf2 nuclear accumulation, thereby exacerbates AKI. These findings suggest that NAD+/SIRT1/GSK‐3β/Nrf2 axis is an important mechanism that can protect against AKI which might be a potential therapeutic target for the treatment of AKI.

POS-057 Production of the regulatory cytokine IL-10 in renal ischemia-reperfusion injury

Acute kidney injury causes irreversible renal tissue damage, the main reason of which is tubulointerstitial damage, and there are few reports on the repair process. It has been reported that Interleukin-10 (IL-10) may inhibit renal dysfunction in acute kidney injury, but its major producing cells are still uncleared. Our purpose is Identification of IL-10 major producing cells in a mouse model of renal ischemia-reperfusion injury.

Acute Kidney Injury and Organ Dysfunction: What Is the Role of Uremic Toxins?

Acute kidney injury (AKI), defined as an abrupt increase in serum creatinine, a reduced urinary output, or both, is experiencing considerable evolution in terms of our understanding of the pathophysiological mechanisms and its impact on other organs. Oxidative stress and reactive oxygen species (ROS) are main contributors to organ dysfunction in AKI, but they are not alone. The precise mechanisms behind multi-organ dysfunction are not yet fully accounted for. The building up of uremic toxins specific to AKI might be a plausible explanation for these disturbances. However, controversies have arisen around their effects in organs other than the kidney, because animal models usually depict AKI as a kidney-specific injury. Meanwhile, humans present AKI frequently in association with multi-organ failure (MOF). Until now, medium-molecular-weight molecules, such as inflammatory cytokines, have been proven to play a role in endothelial and epithelial injury, leading to increased permeability and capillary leakage, mainly in pulmonary and intestinal tissues.

Reference Values of Spot Urine Creatinine-to-Osmolality Ratio : A Cross-Sectional Study of 3,316 Adults in the National Health and Nutrition Examination Survey (NHANES)

Background: Until now, no practical methods for assessment of momentary excretion dysfunction in acute kidney injury (AKI) are available. A spot urine creatinine-to-osmolality ratio (SpotUCrOsm) is an indicator of near real-time renal creatinine (Cr) excretion rate. To introduce its physiological rationales and appications in AKI, we first investigated its reference values and influential factors. Methods: An open database, the National Health and Nutrition Examination Survey (NHANES) 2011–2012, was adopted. The NHANES population included the non-institutionalized civilian residents of the United States. Parameters of interest included demographics, comorbidities, medication use, blood biochemistry data, and spot urine profiles. The original data set from 9,756 individuals were filtered with age and reasonable ranges of relevant anthropometrics and laboratory results. Findings: Of the eligible 3,316 adults, the age in year (mean ± SD) was 45∙2 ± 17∙2 (ranging 18∙0–79∙9); female, 45∙02%; body weight (BW) in Kg, 76 ∙ 1 ± 14∙5 (39∙3–125∙7); and, African American, 23∙6 %. Blood urea nitrogen (BUN, mg/dL) was 12∙6 ± 4∙7 (2-57); serum creatinine (SCr, mg/dL), 0∙89 ± 0∙34 (0∙38–7∙46). As spot urine creatinine (mg/dl) and osmolality (mOsm/Kg) were 127∙1 ± 84∙0 (5–641) and 649 ± 266 (59–1292), respectively, SpotUCrOsm was 0∙19 ± 0∙08 (0∙02–0∙90). With conditioned multivariable regression analysis, estimated personalized SpotUCrOsm (epSpotUCrOsm) = 0∙153 × (age in year)-0∙069 × (BW in kg)0∙281 × 1∙245 [if African American] × (BUN in mg/dL)-0∙310 × (SCr in mg/dL)0∙678. The ratio of SpotUCrOsm to epSpotUCrOsm was 1∙06 ± 0∙40 (0∙14–4∙75). Interpretation: The cutoffs of SpotUCrOsm for early warning of AKI risks may be tentatively set as 0.11 for absolute values and 0∙66 times epSpotUCrOsm for relative ratios. With respective SpotUCrOsm simultaneously lower than the cutoffs, approximately 8.7% of people will be regarding as at risk of having AKI. Funding: None to be declared. Declaration of Interest: None to be declare. Ethical Approval: The NHANES 2011–2012 was approved by the institutional review board of the National Center for Health Statistics. Oral and written informed consent was obtained from all participants.

Mitochondrial dysfunction in kidney injury, inflammation, and disease: Potential therapeutic approaches.

Mitochondria are energy-producing organelles that not only satisfy the high metabolic demands of the kidney but sense and respond to kidney injury-induced oxidative stress and inflammation. Kidneys are rich in mitochondria. Mitochondrial dysfunction plays a critical role in the progression of acute kidney injury and chronic kidney disease. Mitochondrial responses to specific stimuli are highly regulated and synergistically modulated by tightly interconnected processes, including mitochondrial dynamics (fission, fusion) and mitophagy. The counterbalance between these processes is essential in maintaining a healthy network of mitochondria. Recent literature suggests that alterations in mitochondrial dynamics are implicated in kidney injury and the progression of kidney diseases. A decrease in mitochondrial fusion promotes fission-induced mitochondrial fragmentation, but a reduction in mitochondrial fission produces excessive mitochondrial elongation. The removal of dysfunctional mitochondria by mitophagy is crucial for their quality control. Defective mitochondrial function disrupts cellular redox potential and can cause cell death. Mitochondrial DNA derived from damaged cells also act as damage-associated molecular patterns to recruit immune cells and the inflammatory response can further exaggerate kidney injury. This review provides a comprehensive overview of the role of mitochondrial dysfunction in acute kidney injury and chronic kidney disease. We discuss the processes that control mitochondrial stress responses to kidney injury and review recent advances in understanding the role of mitochondrial dysfunction in inflammation and tissue damage through the use of different experimental models of kidney disease. We also describe potential mitochondria-targeted therapeutic approaches.

The Nephroprotective Effect of TNF Receptor-Associated Factor 6 (TRAF6) Blockade on LPS-Induced Acute Renal Injury Through the Inhibition if Inflammation and Oxidative Stress.

BackgroundInflammation and oxidative stress play important roles in the pathogenesis of acute kidney injury (AKI). TRAF6 functions as a signal transducer in the Toll-like receptor 4 signaling pathway. Several reports have previously implicated TRAF6 signaling in kidney pathology. Here, we investigated whether TRAF6 blockade can mitigate inflammatory responses and oxidative stress in AKI.Material/MethodsC57BL/6 mice were injected with lipopolysaccharide (LPS, 15 mg/kg) to induce AKI. Double immunofluorescence staining of kidney tissues showed that TRAF6 was localized to renal tubular epithelial cells, and then a tubular epithelial cell line (NRK-52E) was used for in vitro analysis. TRAF6 was blocked in vitro using siRNA and in vivo using AAV2/2 shRNA.ResultsThe knockdown of TRAF6 in mice by AAV2-shTRAF6 significantly reduced renal inflammation, oxidative stress, apoptosis and kidney dysfunction in AKI. In vitro, silencing the expression of TRAF6 attenuated LPS(0.5 μg/mL)-induced inflammatory responses and oxidative stress and upregulated proapoptotic factors. Furthermore, the beneficial actions of TRAF6 blockade were closely associated with its ability to increase IκB-α and Nrf2.ConclusionsOur findings provide direct evidence that TRAF6 mediates LPS-induced inflammation and oxidative stress, leading to renal dysfunction. We also show that TRAF6 inhibition is a potential therapeutic option to prevent AKI.

Distant organ dysfunction in acute kidney injury.

Acute kidney injury (AKI) is a common complication in critically ill patients and it is associated with increased morbidity and mortality. Epidemiological and clinical data show that AKI is linked to a wide range of distant organ injuries, with the lungs, heart, liver, and intestines representing the most clinically relevant affected organs. This distant organ injury during AKI predisposes patients to progression to multiple organ dysfunction syndrome and ultimately, death. The strongest direct evidence of distant organ injury occurring in AKI has been obtained from animal models. The identified mechanisms include systemic inflammatory changes, oxidative stress, increases in leucocyte trafficking and the activation of proapoptotic pathways. Understanding the pathways driving AKI-induced distal organ injury are critical for the development and refinement of therapies for the prevention and attenuation of AKI-related morbidity and mortality. The purpose of this review is to summarize both clinical and preclinical studies of AKI and its role in distant organ injury.

Mitochondrial Damage and Mitochondria-Targeted Antioxidant Protection in LPS-Induced Acute Kidney Injury.

Induced and frequently unwanted alterations in the mitochondrial structure and functions are a key component of the pathological cascade in many kidney pathologies, including those associated with acute damage. One of the principal pathogenic elements causing mitochondrial dysfunction in Acute Kidney Injury (AKI) is oxidative stress. After ischemia and nephrotoxic action of drugs, sepsis and systemic inflammation are the most frequent causes of AKI. As the kidney suffers from oxidative stress during sepsis, one of the most promising approaches to alleviate such damaging consequences is the use of antioxidants. Considering administration of lipopolysaccharide (LPS) as a model of sepsis, we demonstrate that the mitochondria of neonatal renal tissue are severely affected by LPS-induced AKI, with pathological ultrastructural changes observed in both the mitochondria of the renal tubular epithelium and the vascular endothelium. Upon mitochondrial damage, we evaluated the effect of the mitochondria-targeted antioxidant plastoquinol decylrhodamine 19 (SkQR1) on the development of acute renal failure in newborn rats associated with systemic inflammation induced by the administration of LPS. We found that SkQR1 administration 3 h before LPS led to decreased urinal expression of the AKI marker neutrophil gelatinase-associated lipocalin 2 (NGAL), in addition to a decrease in urea and creatinine levels in the blood. Additionally, an observed impairment of proliferative activity in the neonatal kidney caused by LPS treatment was also prevented by the treatment of rat pups with SkQR1. Thus, one of the key events for renal tissue damage in neonatal sepsis is an alteration in the structure and function of the mitochondria and the mitochondria-targeted antioxidant SkQR1 is an effective nephroprotective agent, which protects the neonatal kidney from sepsis-induced AKI.

The Mental Health from the Self-Regulation Perspective; What Research on Heart Rate Variability Revealed about the Interaction between Self-Regulation and Executive Attention Dysfunction In Acute Kidney Injury And Sex-Specific Implications

Dysfunctional self-regulation has been proposed to be the hallmark of almost all types of poor mental health. Although many prominent researchers have emphasized the role that executive attention control plays in self-regulation, the link between the two in mental health has been less apparent. According to the neurovisceral integration model, cardiac vagal tone, which refers to the parasympathetic influence on the heart at rest, can indicate the functional integrity of self- regulatory systems. A series of recent experiments demonstrate how individual differences in cardiac vagal tone indexed by heart rate variability (HRV) were associated with a varying degree of attentional control to emotional stimuli. The current paper reviewed recent research findings that showed how HRV modulated key components of executive control. These new findings provide evidence linking self-regulatory capacity and executive control, which may play an important role in supporting healthy mental health. American Psychiatric Association defines mental illnesses as “health conditions involving changes in emotion, thinking or behavior (or a combination of these). Mental illnesses are associated with distress and/or problems functioning in social, work or family activities.” 2 Unfortunately, the number of people affected by mental illness is staggering and increasing at an alarming rate. According to the American Psychiatric Association 2 , nearly one in five (19 percent) U.S. adults experience some form of mental illness in a given year. One in 24 (4.1 percent) percent of individuals are being diagnosed with debilitating mental illnesses such as schizophrenia, bipolar disorder, or major depression and one in 12 (8.5 percent) with a substance use disorder. There is a growing body of literature showing that dysfunctional self-regulation is one of the important contributing factors of the etiology and maintenance of various mental illness. 1, 2-6 Self- regulation refers to the ability to regulate cognition, emotion, and behavior to make an adaptive response to meet constantly changing environmental demands, which has been recognized as a key concept that helps understand human development and psychopathologies. 1, 7-9, 10-11 Of particular interest is the link between attention and self-regulation. Attention involves selecting and focusing on information, which shapes and guides thoughts and actions. 10, 12-13 Also, attention plays a critical role in producing self-regulatory responses not only by selecting and focusing on stimuli in the physical environment but also by internally modulating cognitive processes of different information processing. 10

Mitochondrial Haplogroup and the Risk of Acute Kidney Injury Following Cardiac Bypass Surgery

Although mitochondrial dysfunction plays a key role in the pathophysiology of acute kidney injury (AKI), the influence of mitochondrial genetic variability in this process remains unclear. We explored the association between the risk of post-cardiac bypass AKI and mitochondrial haplotype – inherited mitochondrial genomic variations of potentially functional significance. Our single-centre study recruited consecutive patients prior to surgery. Exclusions included stage 5 CKD, non-Caucasian race and subsequent off-pump surgery. Haplogroup analysis allowed characterisation of the study population using the common mutations and by phylogenetic supergroup (WXI and HV). Chi-square tests for association allowed the identification of potential predictors of AKI for use in logistic regression analysis. AKI occurred in 12.8% of the study population (n = 881; male 69.6%, non-diabetic 78.5%, median (interquartile range) age 68.0 (61.0–75.0) years). The haplogroup profile comprised H (42.7%), J (12.1%), T (10.9%), U (14.4%) and K (7.6%). Although the regression model was statistically significant (χ2 = 95.483, p < 0.0005), neither the phylogenetic supergroups nor any individual haplogroup was a significant contributor. We found no significant association between common European haplogroups and the risk of post-cardiac bypass AKI. However, given the major role of mitochondrial dysfunction in AKI, there is a need to replicate our findings in other cohorts and with other aetiologies of AKI.