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Introduction: Remote ischemic conditioning upregulates endogenous protective pathways in response to ischemia-reperfusion injury. This study tested the hypothesis that limb remote ischemic per- conditioning (RIPerC) exerts cardioprotective effects via the renin-angiotensin system (RAS)/inducible nitric oxide synthase (iNOS)/apelin pathway. Methods: Renal ischemia-reperfusion injury (I/R) was induced by bilateral occlusion of the renal pedicles for 60 minutes, followed by 24 hours of reperfusion; sham-operated rats served as controls. RIPerC was induced by four cycles (5 minutes) of limb ischemia-reperfusion along with bilateral renal ischemia. The functional disturbance was evaluated by renal (BUN and creatinine) and cardiac (troponin I and lactate dehydrogenase) injury biomarkers. Results: Renal I/R injury increased renal and cardiac injury biomarkers that were reduced in the RIPerC group. Histopathological findings of the kidney and heart were also suggestive of amelioration injury-induced changes in the RIPerC group. Assessment of cardiac electrophysiology revealed that RIPerC ameliorated the decline in P wave duration without significantly affecting other cardiac electrophysiological changes. Further, renal I/R injury increased the plasma (322.40±34.01 IU/L), renal (8.27±1.10 mIU/mg of Protein), and cardiac (68.28±10.28 mIU/mg of protein) angiotensin-converting enzyme (ACE) activities in association with elevations in the plasma and urine nitrite (25.47±2.01 & 16.62±3.05 μmol/L) and nitrate (15.47±1.33 & 5.01±0.96 μmol/L) levels; these changes were reversed by RIPerC. Further, renal ischemia-reperfusion injury significantly (P =0.047) decreased the renal (but not cardiac) apelin mRNA expression, while renal and cardiac ACE2 (P <0.05)>P=0.043) mRNA expressions were significantly increased compared to the sham group; these effects were largely reversed by RIPerC. Conclusion: Our results indicated that RIPerC protects the heart against renal ischemia- reperfusion injury, likely via interaction of the apelin with the RAS/iNOS pathway. [ABSTRACT FROM AUTHOR]

Objective To investigate the reparative role of dexmedetomidine (Dex) in lung injury secondary to acute kidney injury (AKI). Methods A total of 75 healthy SPF male C57BL/6J mice (6-8 weeks old, weighing 20-22 g) were randomly divided into Sham group (standard laparotomy), renal ischemia reperfusion group (RIR, clamping of bilateral renal pedicles for 50 min followed by reperfusion), and Dex pretreatment group (Dex+RIR, intraperitoneal injection of 25 μg/kg Dex 15 min before bilateral renal pedicle clamping). Lung tissues, bronchoalveolar lavage fluid (BALF), and carotid arterial blood samples were collected from 5 mice in each group at 24, 48, 72, 96, and 120 h after modeling. Lung injury and repair, arterial blood partial pressure of oxygen (PaO2), and BALF contents of transforming growth factor β1 (TGF-β1) and connective tissue growth factor (CTGF) were observed and detected for comparison in the groups at different time points. Reverse transcription quantitative real-time polymerase chain reaction (RT-qPCR) was used to detect the transcript levels of interleukin-6(IL-6) and lung surfactant protein C (SP-C). Results Within 48 h after AKI, lung injury score was increased and PaO2 was decreased in the RIR group and Dex+RIR group than the Sham group, but Dex pretreatment reversed the lung injury score and PaO2 level when compared with the RIR group. The lung injury score was still in a high level and PaO2 stayed low in the RIR group within 96 h after AKI, whereas the 2 indicators in the Dex+RIR group showed a sustained improvement in 48 h after injury. After AKI, the BALF contents of TGF-β1 and CTGF and mRNA level of IL-6 in lung tissue showed a decreasing trend from high level to low level in the RIR group, but all of them were significantly higher than those in the Sham group (P < 0.05), while Dex intervention resulted in an obvious decrease of TGF-β1 at 24-120 h (P < 0.01) and a notable reduction of IL-6 mRNA level at 24-72 h (P < 0.05), whereas a raising trend and maintenance of high level in CTGF at 48-96 h. After AKI, the mRNA level of SP-C in the RIR group were up-regulated at 24 h (P < 0.001, when compared to the Sham group) and then diminished to a low level at 48-120 h (P < 0.05, when compared to the RIR group at 24 h), however Dex pretreatment could alleviate the transcriptional repression of SP-C caused by AKI. Conclusion Dex can ameliorate pulmonary ventilation after lung injury secondary to AKI, and then advance the time for lung repair from 96-120 h to 48-72 h.

Diabetes patients are more prone to acute kidney injury (AKI). Endopeptidases known as matrix metalloproteinases (MMPs) cause extracellular matrix destruction and are responsible for ischemic organ damage. Diabetic nephropathy (DN) affects almost one third of all diabetic patients. MMP-2 and MMP-9 lead to the breakdown of the basement membrane of the glomeruli and thereby the advancement of ischemic injury in diabetes. In addition, histone deacetylase-2 (HDAC-2) is the primary regulator of important signalling processes in the diabetic kidney. A possible treatment approach for diabetic kidney preservation is the flavonoid luteolin (LT), which has anti-inflammatory and antioxidant effects. Our aim was to investigate the renoprotective potential of LT in diabetes by modulating MMP-2, MMP-9 and HDAC-2 activity. The expression of MMP-2, MMP-9 and HDAC-2 were statistically higher in streptozotocin-induced diabetic rat renal homogenate after renal ischemic reperfusion injury. These changes were reversed with 2 weeks of pre-treatment with LT (50 mg/kg po). In diabetic rats, pre-treatment with LT significantly reduced oxidative stress, inflammation and fibrosis compared to control animals. Preventive LT prior to renal ischemia showed improvement in body weight, kidney weight/body weight ratio, reversal of renal injury and biochemical changes with lower activity of malondialdehyde (MDA), myeloperoxidase (MPO), hydroxyproline (HP), pathological damage and fibrosis in renal tissue. Our data imply that LT prevents DN in rats by inhibiting MMP-2, MMP-9 and HDAC-2 expression, as well as by lowering the indices of oxidative stress, pro-inflammatory factors and fibrosis.

Ferroptosis is involved in various tissue injuries including neurodegeneration, ischemia-reperfusion injury, and acute liver injury. Ferroptosis inhibitors exhibit promising clinical potential in the treatment of various diseases. As a traditional chemical, silymarin has been widely used in healthcare and clinical applications to treat liver injuries in which ferroptosis is involved. Silibinin is the main active ingredient of silymarin. However, the effect of silibinin on ferroptosis and ferroptosis-related diseases remains unclear. Here, we found that silibinin inhibited death in different kinds of cells caused by ferroptosis inducers including RSL3 and erastin. Moreover, silibinin alleviated lipid peroxidation induced by RSL3 without affecting the labile iron pool. Next, the antioxidant activity of silibinin was demonstrated by the DPPH assay. In vivo, silibinin strikingly relieved tissue injuries and ferroptosis in the liver and kidney of glutathione peroxidase 4 (GPX4) knockout C57 BL/6J mice. Moreover, silibinin effectively rescued renal ischemia-reperfusion, a well-known ferroptosis-related disease. In conclusion, our study revealed that silibinin effectively inhibits cell ferroptosis and ferroptosis-related tissue injuries, implicating silibinin as a potential chemical to treat ferroptosis-related diseases. [ABSTRACT FROM AUTHOR]

Introduction: Remote ischemic conditioning upregulates endogenous protective pathways in response to ischemia-reperfusion injury. This study tested the hypothesis that limb remote ischemic per- conditioning (RIPerC) exerts cardioprotective effects via the renin-angiotensin system (RAS)/inducible nitric oxide synthase (iNOS)/apelin pathway. Methods: Renal ischemia-reperfusion injury (I/R) was induced by bilateral occlusion of the renal pedicles for 60 minutes, followed by 24 hours of reperfusion; sham-operated rats served as controls. RIPerC was induced by four cycles (5 minutes) of limb ischemia-reperfusion along with bilateral renal ischemia. The functional disturbance was evaluated by renal (BUN and creatinine) and cardiac (troponin I and lactate dehydrogenase) injury biomarkers. Results: Renal I/R injury increased renal and cardiac injury biomarkers that were reduced in the RIPerC group. Histopathological findings of the kidney and heart were also suggestive of amelioration injury-induced changes in the RIPerC group. Assessment of cardiac electrophysiology revealed that RIPerC ameliorated the decline in P wave duration without significantly affecting other cardiac electrophysiological changes. Further, renal I/R injury increased the plasma (322.40±34.01 IU/L), renal (8.27±1.10 mIU/mg of Protein), and cardiac (68.28±10.28 mIU/mg of protein) angiotensin-converting enzyme (ACE) activities in association with elevations in the plasma and urine nitrite (25.47±2.01 & 16.62±3.05 μmol/L) and nitrate (15.47±1.33 & 5.01±0.96 μmol/L) levels; these changes were reversed by RIPerC. Further, renal ischemia-reperfusion injury significantly (P=0.047) decreased the renal (but not cardiac) apelin mRNA expression, while renal and cardiac ACE2 (P

Cyclosporine A (CsA) preconditioning is known to target mitochondrial permeability transition pore and protect renal function after ischemia reperfusion (IR). The upregulation of heat-shock protein 70 (Hsp70) expression after CsA injection is thought to be associated with renal protection. The aim of this study was to test the effect of Hsp70 expression on kidney and mitochondria functions after IR. Mice underwent a right unilateral nephrectomy and 30 min of left renal artery clamping, performed after CsA injection and/or administration of the Hsp70 inhibitor. Histological score, plasma creatinine, mitochondrial calcium retention capacity, and oxidative phosphorylation were assessed after 24 h of reperfusion. In parallel, we used a model of hypoxia reoxygenation on HK2 cells to modulate Hsp70 expression using an SiRNA or a plasmid. We assessed cell death after 18 h of hypoxia and 4 h of reoxygenation. CsA significantly improved renal function, histological score, and mitochondrial functions compared to the ischemic group but the inhibition of Hsp70 repealed the protection afforded by CsA injection. In vitro, Hsp70 inhibition by SiRNA increased cell death. Conversely, Hsp70 overexpression protected cells from the hypoxic condition, as well as the CsA injection. We did not find a synergic association between Hsp70 expression and CsA use. We demonstrated Hsp70 could modulate mitochondrial functions to protect kidneys from IR. This pathway may be targeted by drugs to provide new therapeutics to improve renal function after IR. [ABSTRACT FROM AUTHOR]

Abstract Background Acute renal injury (AKI) secondary to ischemia reperfusion (IR) injury continues to be a significant perioperative problem and there is no effective treatment. Mindin belongs to the mindin/F-spondin family and involves in inflammation, proliferation, and cell apoptosis. Previous studies have explored the biological functions of mindin in liver and brain ischemic injury, but its role in AKI is unknown. Method To investigate whether mindin has a pathogenic role, mindin knockout (KO) and wild-type (WT) mice were used to establish renal IR model. After 30 min of ischemia and 24 h of reperfusion, renal histology, serum creatinine, and inflammatory response were examined to assess kidney injury. In vitro, proinflammatory factors and inflammatory signaling pathways were measured in mindin overexpression or knockdown and vector cells after hypoxia/reoxygenation (HR). Results Following IR, the kidney mindin level was increased in WT mice and deletion of mindin provided significant protection for mice against IR-induced renal injury as manifested by attenuated the elevation of serum creatinine and blood urea nitrogen along with less severity for histological alterations. Mindin deficiency significantly suppressed inflammatory cell infiltration, TNF-α and MCP-1 production following renal IR injury. Mechanistic studies revealed that mindin deficiency inhibits TLR4/JNK/NF-κB signaling activation. In vitro, the expression levels of TNF-α and MCP-1 were increased in mindin overexpression cells compared with vector cells following HR. Moreover, TLR4/JNK/NF-κB signaling activation was elevated in the mindin overexpression cells in response to HR stimulation while mindin knockdown inhibited the activation of TLR4/JNK/ NF-κB signaling after HR in vitro. Further study showed that mindin protein interacted directly with TLR4 protein. And more, mindin protein was confirmed to be expressed massively in renal tubule tissues of human hydronephrosis patients. Conclusion These data demonstrate that mindin is a critical modulator of renal IR injury through regulating inflammatory responses. TLR4/JNK/NF-κB signaling most likely mediates the biological function of mindin in this model of renal ischemia.

Ferroptosis is involved in various tissue injuries including neurodegeneration, ischemia-reperfusion injury, and acute liver injury. Ferroptosis inhibitors exhibit promising clinical potential in the treatment of various diseases. As a traditional chemical, silymarin has been widely used in healthcare and clinical applications to treat liver injuries in which ferroptosis is involved. Silibinin is the main active ingredient of silymarin. However, the effect of silibinin on ferroptosis and ferroptosis-related diseases remains unclear. Here, we found that silibinin inhibited death in different kinds of cells caused by ferroptosis inducers including RSL3 and erastin. Moreover, silibinin alleviated lipid peroxidation induced by RSL3 without affecting the labile iron pool. Next, the antioxidant activity of silibinin was demonstrated by the DPPH assay. In vivo, silibinin strikingly relieved tissue injuries and ferroptosis in the liver and kidney of glutathione peroxidase 4 (GPX4) knockout C57 BL/6J mice. Moreover, silibinin effectively rescued renal ischemia-reperfusion, a well-known ferroptosis-related disease. In conclusion, our study revealed that silibinin effectively inhibits cell ferroptosis and ferroptosis-related tissue injuries, implicating silibinin as a potential chemical to treat ferroptosis-related diseases.

Renal ischemia–reperfusion (IR), a routine feature of partial nephrectomy (PN), can contribute to the development of acute kidney injury (AKI). Rodent studies show that the endocannabinoid system (ECS) is a major regulator of renal hemodynamics and IR injury; however, its clinical relevance remains to be established. Here, we assessed the clinical changes in systemic endocannabinoid (eCB) levels induced by surgical renal IR. Sixteen patients undergoing on-clamp PN were included, with blood samples taken before renal ischemia, after 10 min of ischemia time, and 10 min following blood reperfusion. Kidney function parameters (serum creatinine (sCr), blood urea nitrogen (BUN), and serum glucose) and eCB levels were measured. Baseline levels and individual changes in response to IR were analyzed and correlation analyses were performed. The baseline levels of eCB 2-arachidonoylglycerol (2-AG) were positively correlated with kidney dysfunction biomarkers. Unilateral renal ischemia increased BUN, sCr, and glucose, which remained elevated following renal reperfusion. Renal ischemia did not induce changes in eCB levels for all patients pooled together. Nevertheless, stratifying patients according to their body mass index (BMI) revealed a significant increase in N-acylethanolamines (anandamide, AEA; N-oleoylethanolamine, OEA; and N-palmitoylethanolamine, PEA) in the non-obese patients. No significant changes were found in obese patients who had higher N-acylethanolamines baseline levels, positively correlated with BMI, and more cases of post-surgery AKI. With the inefficiency of 'traditional' IR-injury 'preventive drugs', our data support future research on the role of the ECS and its manipulation in renal IR. [ABSTRACT FROM AUTHOR]

Background: Acute renal injury (AKI) secondary to ischemia reperfusion (IR) injury continues to be a significant perioperative problem and there is no effective treatment. Mindin belongs to the mindin/F-spondin family and involves in inflammation, proliferation, and cell apoptosis. Previous studies have explored the biological functions of mindin in liver and brain ischemic injury, but its role in AKI is unknown. Method: To investigate whether mindin has a pathogenic role, mindin knockout (KO) and wild-type (WT) mice were used to establish renal IR model. After 30 min of ischemia and 24 h of reperfusion, renal histology, serum creatinine, and inflammatory response were examined to assess kidney injury. In vitro, proinflammatory factors and inflammatory signaling pathways were measured in mindin overexpression or knockdown and vector cells after hypoxia/reoxygenation (HR). Results: Following IR, the kidney mindin level was increased in WT mice and deletion of mindin provided significant protection for mice against IR-induced renal injury as manifested by attenuated the elevation of serum creatinine and blood urea nitrogen along with less severity for histological alterations. Mindin deficiency significantly suppressed inflammatory cell infiltration, TNF-α and MCP-1 production following renal IR injury. Mechanistic studies revealed that mindin deficiency inhibits TLR4/JNK/NF-κB signaling activation. In vitro, the expression levels of TNF-α and MCP-1 were increased in mindin overexpression cells compared with vector cells following HR. Moreover, TLR4/JNK/NF-κB signaling activation was elevated in the mindin overexpression cells in response to HR stimulation while mindin knockdown inhibited the activation of TLR4/JNK/ NF-κB signaling after HR in vitro. Further study showed that mindin protein interacted directly with TLR4 protein. And more, mindin protein was confirmed to be expressed massively in renal tubule tissues of human hydronephrosis patients. Conclusion: These data demonstrate that mindin is a critical modulator of renal IR injury through regulating inflammatory responses. TLR4/JNK/NF-κB signaling most likely mediates the biological function of mindin in this model of renal ischemia. [ABSTRACT FROM AUTHOR]

Introduction: Penehyclidine hydrochloride (PHC) is an anticholinergic with anti-inflammatory and anti-oxidation activities. PHC displayed protectivity against renal ischemia reperfusion (RIR) injury. Nevertheless, the precise protectivity of PHC on RIR-induced lung injury remains unknown. Methods: We examined the effects of PHC on RIR-induced lung injury and investigated the underlying mechanism. We induced RIR in mice and administrated PHC to RIR mice. Kidney function was monitored by measuring the blood urea nitrogen (BUN) and creatinine level in serum. We evaluated the lung injury, myeloperoxidase (MPO) activity in lung, pro-inflammatory cytokine level, and oxidative markers in serum and lung tissues. We tested the expression level of nuclear factor erythroid 2-related factor 2 (Nrf-2) and heme oxygenase 1 (HO-1) in lung of RIR mice after PHC treatment. Finally, we evaluated the effects of PHC in RIR Nrf2-/- mice. Results: PHC greatly downregulated the serum levels of BUN, creatinine, IL-6, NO, malondialdehyde (MDA), and matrix metalloproteinase-2. PHC also ameliorated the lung injury, decreased the MPO activity, and suppressed production of IL-6, TNF-α, IFN-γ, MDA, and O2-, while it promoted production of superoxide dismutase (SOD) and catalase (CAT) in lung. PHC improved the production of Nrf2 and HO-1. Conclusion: The protectivity of PHC was absent in Nrf2-/- mice. PHC ameliorated RIR-induced lung injury through Nrf2 pathway.

Renal ischemia-reperfusion injury (IRI) is the main cause of acute kidney injury and the cause of rapid renal dysfunction and high mortality. In recent years, with the gradual deepening of the understanding of the intestinal flora, exploring renal IRI from the perspective of the intestinal flora has become a research hotspot. It is well known that the intestinal flora plays an important role in maintaining human health, and dysbiosis is the change in the composition and function of the intestinal tract, which in turn causes intestinal barrier dysfunction. Studies have shown that there are significant differences in the composition of intestinal flora before and after renal IRI, and this difference is closely related to the occurrence and development of renal IRI and affects prognosis. In addition, toxins produced by dysregulated gut microbes enter the bloodstream, which in turn exacerbates kidney damage. This article reviews the research progress of intestinal flora and renal IRI, in order to provide new treatment ideas and strategies for renal IRI. [ABSTRACT FROM AUTHOR]

Cyclosporine A (CsA) preconditioning is known to target mitochondrial permeability transition pore and protect renal function after ischemia reperfusion (IR). The upregulation of heat-shock protein 70 (Hsp70) expression after CsA injection is thought to be associated with renal protection. The aim of this study was to test the effect of Hsp70 expression on kidney and mitochondria functions after IR. Mice underwent a right unilateral nephrectomy and 30 min of left renal artery clamping, performed after CsA injection and/or administration of the Hsp70 inhibitor. Histological score, plasma creatinine, mitochondrial calcium retention capacity, and oxidative phosphorylation were assessed after 24 h of reperfusion. In parallel, we used a model of hypoxia reoxygenation on HK2 cells to modulate Hsp70 expression using an SiRNA or a plasmid. We assessed cell death after 18 h of hypoxia and 4 h of reoxygenation. CsA significantly improved renal function, histological score, and mitochondrial functions compared to the ischemic group but the inhibition of Hsp70 repealed the protection afforded by CsA injection. In vitro, Hsp70 inhibition by SiRNA increased cell death. Conversely, Hsp70 overexpression protected cells from the hypoxic condition, as well as the CsA injection. We did not find a synergic association between Hsp70 expression and CsA use. We demonstrated Hsp70 could modulate mitochondrial functions to protect kidneys from IR. This pathway may be targeted by drugs to provide new therapeutics to improve renal function after IR.

Introduction: Penehyclidine hydrochloride (PHC) is an anticholinergic with anti-inflammatory and anti-oxidation activities. PHC displayed protectivity against renal ischemia reperfusion (RIR) injury. Nevertheless, the precise protectivity of PHC on RIR-induced lung injury remains unknown. Methods: We examined the effects of PHC on RIR-induced lung injury and investigated the underlying mechanism. We induced RIR in mice and administrated PHC to RIR mice. Kidney function was monitored by measuring the blood urea nitrogen (BUN) and creatinine level in serum. We evaluated the lung injury, myeloperoxidase (MPO) activity in lung, pro-inflammatory cytokine level, and oxidative markers in serum and lung tissues. We tested the expression level of nuclear factor erythroid 2-related factor 2 (Nrf-2) and heme oxygenase 1 (HO-1) in lung of RIR mice after PHC treatment. Finally, we evaluated the effects of PHC in RIR Nrf2-/- mice. Results: PHC greatly downregulated the serum levels of BUN, creatinine, IL-6, NO, malondialdehyde (MDA), and matrix metalloproteinase-2. PHC also ameliorated the lung injury, decreased the MPO activity, and suppressed production of IL-6, TNF-α, IFN-γ, MDA, and O2-, while it promoted production of superoxide dismutase (SOD) and catalase (CAT) in lung. PHC improved the production of Nrf2 and HO-1. Conclusion: The protectivity of PHC was absent in Nrf2-/- mice. PHC ameliorated RIR-induced lung injury through Nrf2 pathway. [ABSTRACT FROM AUTHOR]

Renal ischemia-reperfusion (I-R) injury is the main cause of acute renal failure. Acute pancreatitis is one of the fatal remote lesions that occurs in patients with renal I-R injury. Platelet-rich plasma (PRP) is a hopeful aiding therapy for tissue injuries. Forty adult rats were utilized in this study, ten for PRP preparation and thirty were divided into three groups; Control: subdivided into three equal subgroups, I-R group: exposed to bilateral renal pedicles clamping and I-R+ PRP group: were experienced identical procedures as I-R group then subcutaneously (S.C) injected with 0.5 ml PRP two times weekly for three weeks. Blood samples were taken for detection of serum urea and creatinine, blood glucose level and serum amylase. The pancreas was dissected and prepared for histopathological examination by light and electron microscope. Statistical analysis of all collected results was performed. Our biochemical results revealed deleterious effects of renal I-R on the pancreas as evidenced by a highly significant increase in serum amylase and blood glucose level. In I-R group, histopathological examination revealed wide septa and congested blood vessels, acinar cells showed disrupted rough endoplasmic reticulum and few secretory granules. Some islet cells showed pyknotic nuclei and vacuolated cytoplasm. PRP treated group showed nearly normal structure in the form of numerous acinar cells' granules, extensive rough endoplasmic reticulum and mitochondria. Most of Beta cells had euchromatic nuclei and numerous secretory granules. Accordingly, PRP treatment reduced the pancreatic biochemical and histopathological alterations caused by renal I-R injury and so considered a promising therapy for pancreatic damage. [ABSTRACT FROM AUTHOR]

Introduction Ischemic preconditioning (Ipre) provides protection against renal ischemia-reperfusion (I/R) injury with its associated remote organ damage. This study examined the enhancing protective effect of Ipre with levosimendan or cilostazol in I/R-induced kidney and lung injury in a rat model. Material and methods Rats were divided into: sham-operated, I/R control, Ipre control, I/R + cilostazol or levosimendan and Ipre + cilostazol or levosimendan. Drugs were given 30 min before left renal I/R or 4 cycles of Ipre just before renal ischemia. Results The Ipre combined with the implemented drugs enhanced physio­logical antioxidant defense genes including renal nuclear factor erythroid 2-related factor 2 (Nrf2) and its dependent genes heme oxygenase-1 (HO-1) and NADPH-quinone oxidoreductase-1 (NQO-1) and improved malondialdehyde and superoxide dismutase renal tissue levels. The combined effect improved I/R consequences for blood urea, creatinine, and creatinine clearance and improved blood oxygenation and metabolic acidosis. Moreover, the combination improved the renal soluble intercellular adhesion molecule (ICAM), tumor necrosis factor  (TNF-) and interlukin-6 (IL-6) with histopathological improvement of tubular necrosis with a decrease in the apoptotic marker caspase-3 and an increase in the anti-apoptotic Bcl-2 expression. Conclusions Cilostazol or levosimendan potentiates the renoprotective effect of Ipre against renal I/R injury, associated with upregulation of antioxidant genes Nrf2, HO-1, and NOQ-1 expression.

Acute kidney injury (AKI) induced by renal ischemia reperfusion (RIR) is typically observed in renal surgeries and is a leading cause of renal failure. However, there is still an unmet medical need currently in terms of clinical treatments. Herein, we report the effect of Urolithin A (UA) in a mouse RIR model, wherein we demonstrated its underlying mechanism both in vitro and in vivo. The expression levels of p62 and Keap1 significantly decreased, while that of nuclear Nrf2 increased in vitro in a hypoxia cell model after UA treatment. Furthermore, the apoptosis of tubular cells was attenuated and the reactive oxygen species (ROS) levels were reduced in the kidneys in a mouse RIR model after UA administration. In this study, we demonstrated that UA can alleviate oxidative stress and promote autophagy by activating the p62-Keap1-Nrf2 signaling pathway, which could protect the kidneys from ischemia reperfusion injury. [ABSTRACT FROM AUTHOR]

Objective To explore the effects of dexmedetomidine (Dex) on systemic inflammatory response induced by renal ischemia reperfusion (rIRI) and the possible mechanism. Methods Fifteen C57BL/6J mice were randomly divided into 3 groups, that is, sham operation group (laparotomy without renal pedicle occlusion), rIRI group (bilateral renal pedicles was clamped for 60 min with a microvascular clamp), and rIRI+Dex group (intraperitoneal injection of 25 μg/ml Dex in 15 min prior to bilateral renal ischemia). In 24 h after surgery or reperfusion, the blood samples were harvested and analyzed for counts of neutrophils, monocytes and lymphocytes by blood analyzer and for the serum levels of inflammatory cytokines (TNF-α, IL-1β and IL-10) by ELISA. Western blotting was used to detect iNOS and Arg 1 in the harvested peritoneal macrophages for the polarization. Results Compared with the mice in the sham group, the counts of neutrophils, monocytes and lymphocytes were significantly elevated (P < 0.01), the serum levels of TNF-α and IL-1β were increased (P < 0.01), and the expression of M1 marker iNOS was enhanced while that of M2 marker Arg 1 was decreased (P < 0.01). Dex pretreatment resulted in no significant changes in the counts of neutrophils, monocytes and lymphocytes (P>0.05), reduced serum levels of TNF-α and IL-1β (P < 0.01) and increased level of IL-10 (P < 0.01), and decreased expression of iNOS (P < 0.01) as well as increase of Arg 1 (P < 0.05) when compared with the indicators in the rIRI group. Conclusion Dex inhibits the systemic inflammatory response induced by rIRI, which may be associated with modulation of macrophage polarization.

Renal ischemia–reperfusion (IR), a routine feature of partial nephrectomy (PN), can contribute to the development of acute kidney injury (AKI). Rodent studies show that the endocannabinoid system (ECS) is a major regulator of renal hemodynamics and IR injury; however, its clinical relevance remains to be established. Here, we assessed the clinical changes in systemic endocannabinoid (eCB) levels induced by surgical renal IR. Sixteen patients undergoing on-clamp PN were included, with blood samples taken before renal ischemia, after 10 min of ischemia time, and 10 min following blood reperfusion. Kidney function parameters (serum creatinine (sCr), blood urea nitrogen (BUN), and serum glucose) and eCB levels were measured. Baseline levels and individual changes in response to IR were analyzed and correlation analyses were performed. The baseline levels of eCB 2-arachidonoylglycerol (2-AG) were positively correlated with kidney dysfunction biomarkers. Unilateral renal ischemia increased BUN, sCr, and glucose, which remained elevated following renal reperfusion. Renal ischemia did not induce changes in eCB levels for all patients pooled together. Nevertheless, stratifying patients according to their body mass index (BMI) revealed a significant increase in N-acylethanolamines (anandamide, AEA; N-oleoylethanolamine, OEA; and N-palmitoylethanolamine, PEA) in the non-obese patients. No significant changes were found in obese patients who had higher N-acylethanolamines baseline levels, positively correlated with BMI, and more cases of post-surgery AKI. With the inefficiency of ‘traditional’ IR-injury ‘preventive drugs’, our data support future research on the role of the ECS and its manipulation in renal IR.

OBJECTIVE: To probe into the effects of tanshinone HA combined with dexmedetomidine on autophagy and apoptosis after renal ischemia reperfusion through AMPK/ULK1 pathway. METHODS: Fifty healthy male Wistar rats were randomly divided into five groups; group A (tanshinone HA + dexmedetomidine), group B ( dexmedetomidine), group C (tanshinone HA), group D (ischemia reperfusion model) and group E ( sham surgery group). The renal ischemia-reperfusion model was established by clamping the bilateral renal pedicles for 45 min. Before ischemia of 30 min, rats in group A were intraperitoneally injected with tanshinone extraction + 25 µg/kg dexmedetomidine, rats in group B were injected intraperitoneally with 25 pg/kg dexmedetomidine, rats in group C were injected intraperitoneally with Danshen injection, rats in group D and E were given the same amount of 0.9% sodium chloride solution. After reperfusion of 24 h, the pathological changes of renal tissue were observed by HE staining method; the expression of AMPK and ULK1 were determined by Western blot; blood samples were taken to determine serum tumor necrosis factor a (TNF-α), interleukin ( IL) 6 and IL-10. RESULTS: The histopathological changes of rats in group A were lighter than those in group D. Apoptosis was not obvious in group E, a large number of apoptotic cells and severe tissue damages were observed in group D, and only scattered apoptotic cells were seen in group A with mild tissue damages. The tissue damages of rats in groups B and C were slight, and a small number of apoptotic cells were visible. Compared with group D, apoptosis index of rats in groups A, B and C decreased significantly, with statistically significant difference (P<0.05). Compared with group D, the expression of AMPK and ULK1 in renal tissues of rats in group A rats decreased significantly, and the differences were statistically significant (P<0.05). Compared with group B, C and D, the levels of IL-6 and TNF-a in group A decreased significantly, while the levels of IL-10 increased significantly, with statistically significant difference (P<0.05). CONCLUSIONS: During renal ischemia reperfusion, tanshinone HA combined with dexmedetomidine can reduce the tissue inflammation, decrease the renal cell apoptosis and alleviate the tissue damage, which may be achieved through inhibition of autophagy levels by AMPK/ULK1 pathway. [ABSTRACT FROM AUTHOR]

Abstract Background Recent researches indicate that the intestinal consequences of renal ischemia reperfusion (IR) would predispose to the translocation of gut-derived endotoxin. Here, we designed experiments to test the hypothesis that the gut-derived endotoxin has a potential role in mediating local inflammatory processes in the acutely injured kidney. Methods Rats were performed sham or renal IR surgery (60 min of bilateral renal ischemia, then 24 h of reperfusion) (n = 5). The intestinal structural and mucosa permeability were evaluated. Serum endotoxin and bacterial load in liver and mesenteric lymph nodes (MLN) were measured. Separate groups were pretreated with oral norfloxacin 20 mg/kg/day or saline for 4 weeks and divided into sham plus saline, sham plus norfloxacin, renal IR plus saline and renal IR plus norfloxacin group. Serum biochemistry and endotoxin were determined. Kidney pathological changes were scored. Protein or mRNA expression of toll-like receptor 4 (TLR4) and proinflammatory mediators were measured in kidney homogenate. Results Renal IR led to marked intestinal integrity disruption and increase in intestinal permeability. These are accompanied by low grade of endotoxemia as well as increased bacterial load in liver and MLN. The group pretreated with norfloxacin showed significant attenuation of the increase in serum urea, ALAT, ASAT and endotoxin. The increased renal protein or mRNA of TLR4 and proinflammatory mediators (IL-6 and MCP-1) in the unpretreated animals was significantly attenuated in the norfloxacin-pretreated animals. However, norfloxacin pretreatment did not produce any protective effects on renal tubular integrity. Conclusions Our results show for the first time that gut-derived endotoxin, resulting from an increased intestinal permeability after severe renal IR, subsequently amplifies intrarenal inflammatory response by activation renal TLR4 signaling. Our study results do not establish that antibiotic administration was effective in improving the overall renal outcome. However, our findings may be the first step to understanding how to tailor therapies to mitigate intrarenal inflammation in select groups of patients.

Acute kidney injury (AKI) is characterized by a rapid and potentially reversible decline in renal function. We hypothesized that Eugenia uniflora (pitanga) may present a protective effect in AKI due to its antioxidant properties. Extract from pitanga leaves (200 mg/kg, gavage) or vehicle was administered to Wistar rats (28 days) prior to AKI induction by 45-minute bilateral renal ischemia. Renal hemodynamic was quantified after 24 h of reperfusion to determine the glomerular filtration rate (GFR), renal blood flow (RBF) and renal vascular resistance (RVR). Renal production of reactive oxygen species and apoptosis, SOD and catalase expression and activity were determined. Treatment with pitanga prevented AKI-induced decrease in GFR and RBF, as well as the rise in RVR. Pitanga also prevented the increased oxidative stress and apoptosis, probably due to a rise in antioxidant enzymes activity and expression. These results demonstrate a protective effect of pitanga extract on AKI development.

Objective To explore the effect and mechanism of sulforaphane on renal ischemia reperfusion injury (IRI) in mice to provide experimental evidence for effective intervention in renal IRI. Methods Totally 24 male C57 mice were randomly divided into four groups: control group (Ctrl), IRI group, sulforaphane intervention IRI group (IRI + SFN), and sulforaphane alone group (SFN). SFN was injected into the mice at the dosage of 500μg/kg 24h before surgery. The renal IRI model was established by using the bilateral renal pedicles of mice with non-invasive vascular clamping for 45min. After 24h of renal blood perfusion, we sacrificed the mice and collected the whole blood and kidney tissue samples for pathological and biological examinations. The levels of TNF-α, IL-1β and IL-6 in murine serum were tested by ELISA. The expression levels of Nrf-2, keap-1, p-iκBα, IκBα and NFκB p-p65 in murine kidney were detected by Western blot. Results Sulforaphane could improve renal function in mice with ischemia reperfusion and reduce apoptosis of renal tubular epithelial cells. Sulforaphane could also decrease the levels of TNF-α, IL-1β and IL-6 in murine serum and increase the expression of Nrf-2 in murine kidney tissue after ischemia reperfusion. Moreover, sulforaphane decreased the expression of p-iκBα in total protein and NFκB p-p65 in nucleus protein of renal tissue. Conclusion Sulforaphane could inhibit phosphorylation, thus inhibiting the phosphorylation of NFκB p65 to translocation into the nucleus. Further it prevented the expressions of downstream inflammatory factors such as TNF-α, IL-1β and IL-6. Finally sulforaphane attenuated renal IRI in mice by Nrf-2 against inflammation. [ABSTRACT FROM AUTHOR]

Aims: Perioperative acute kidney injury (AKI) resulting from renal ischemia reperfusion (IR) is not conducive to the postoperative surgical recovery. Our previous study demonstrated that reactive oxygen species (ROS) transmitted by gap junction (GJ) composed of connexin32 (Cx32) contributed to AKI. However, the precise underlying pathophysiologic mechanisms were largely unknown. This study focuses on the underlying mechanisms related to ROS transmitted by Cx32 responsible for AKI aggravation. Results: In a set of in vivo studies, renal IR was found to cause severe impairment in renal tissues with massive ROS generation, which occurred contemporaneously with activation of NF-κB/p53/p53 upregulated modulator of apoptosis (PUMA)-mediated mitochondrial apoptosis pathways. Cx32 deficiency alleviated renal IR-induced AKI, and simultaneously attenuated ROS generation and distribution in renal tissues, which further inhibited NF-κB/p53/PUMA-mediated mitochondrial apoptotic pathways. Correspondingly, in a set of in vitro studies, hypoxia reoxygenation (HR)-induced cellular injury, and cell apoptosis in both human kidney tubular epithelial cells (HK-2s) and rat kidney tubular epithelial cells (NRK52Es) were significantly attenuated by Cx32 inhibitors or Cx32 gene knockdown. More importantly, Cx32 inhibition not only decreased ROS generation and distribution in human or rat kidney tubular epithelial cells but also inhibited its downstream NF-κB/p53/PUMA-mediated mitochondrial apoptotic pathway activation. Innovation and Conclusion: This is the first identification of the underlying mechanisms of IR-induced renal injury integrally which demonstrates the critical role played by Cx32 in IR-induced AKI. Moreover, GJ composed of Cx32 manipulates ROS generation and distribution between neighboring cells, and alters activation of NF-κB/p53/PUMA-mediated mitochondrial apoptotic pathways. Both inhibiting Cx32 function and scavenging ROS effectively reduce mitochondrial apoptosis and subsequently attenuate AKI, providing effective strategies for kidney protection. [ABSTRACT FROM AUTHOR]

Aim: Ischaemia‐reperfusion (I/R) induces distant organ injury (DOI) via inflammation and oxidative stress. Statins have anti‐inflammatory and anti‐oxidant effects independent of their cholesterol‐lowering properties. To clarify whether statins could suppress DOI, we investigated the effect of rosuvastatin (RO) on the contralateral kidney following unilateral renal I/R. Methods: Dahl salt‐sensitive rats (6 weeks old) were randomly divided into four groups: sham, sham with RO, I/R, and I/R with RO. All rats were fed a high‐salt (8%) diet for 6 weeks. RO (10 mg/kg per day) was pre‐administered by supplementation to the drinking water for 2 weeks before I/R. The rats then underwent unilateral renal I/R (ischemia for 45 min). Three days after I/R, laboratory data, histological changes and protein expression levels of the contralateral kidney were assessed. Results: I/R significantly elevated serum creatinine and malondialdehyde levels and induced a significantly higher glomerular sclerosis index and tubular dilation area of the contralateral kidney, with about 2‐fold infiltration of ED‐1‐positive cells. In the I/R group, protein expression of superoxide dismutase (SOD) of the contralateral kidney was reduced to about 50% of the sham group. RO‐pretreatment significantly suppressed all of these changes following I/R. Conclusion: RO‐pretreatment diminished contralateral kidney injury with the suppression of ED‐1‐positive cell infiltration and SOD reduction after I/R. RO appears to have a protective effect on DOI by its anti‐inflammatory and anti‐oxidant effects. Summary at a Glance: This study investigated the therapeutic effects of the statin, rosuvastatin on distant organ injury in Dahl salt‐sensitive rats subjected to ischemia‐reperfusion (I/R) injury. I/R injury significantly elevated serum creatinine and malondialdehyde levels and induced a significantly higher glomerular sclerosis index and tubular dilation area of the contralateral kidney. Rosuvastatin suppressed all of these changes induced by I/R, suggesting that rosuvastatin can protect from distant organ injury via its anti‐inflammatory and anti‐oxidant effects. [ABSTRACT FROM AUTHOR]

Purpose: Renal ischemia reperfusion (IR) is an important cause of renal dysfunction. It contributes to the development of acute renal failure (ARF). The purpose of this study was to investigate the anti-inflammatory effect of erythropoietin (EPO) and melatonin (MEL), which are known anti-inflammatory and antioxidant agents, in IR-induced renal injury in rats. Methods: Male Wistar Albino rats were unilaterally nephrectomized and subjected to 45 min of renal pedicle occlusion followed by 24 h reperfusion. MEL (10mg/kg, i.p) and EPO (5000U/kg, i.p) were administered prior to ischemia. After 24 h reperfusion, blood samples were collected for the determination of total antioxidant capacity (TAC), malondialdehyde (MDA) and serum creatinine levels. Also, renal samples were taken for Immunohistochemical evaluation of Bcl2 and TNF-α (tumor necrosis factor-α) expression. Results: Ischemia reperfusion increased creatinine, TAC, MDA levels and TNF-α expression, also, IR decreased Bcl2 expression. Treatment with EPO or MEL decreased creatinine, MDA levels, and increased TAC level. Also, MEL up-regulated Bcl2 expression and down-regulated TNF-α expression compared with EPO. Conclusion: Treatment with EPO and MEL had a curative effect on renal IR injury. These results may indicate that MEL protects against inflammation and apoptosis better than EPO in renal IR injury.

Renal ischemia reperfusion (IR) is a major cause of acute kidney injury (AKI) and no effective treatments have been established. Tisp40 is a transcription factor of the CREB/ATF family and involves in cell apoptosis, proliferation and differentiation, but its role in renal IR remains unknown. Here, we investigated the role of Tisp40 in renal IR injury. In vivo, Tisp40 knockout (KO) and wild-type (WT) mice were subjected to thirty minutes of bilateral renal ischemia and 48 h reperfusion, the blood and kidneys were harvested for analysis. In vitro, Tisp40 overexpression and vector cells were subjected to hypoxia/reoxygenation (HR), the apoptosis rate and the expressions of related proteins were measured. Following IR, the expressions of Tisp40 protein, serum creatinine (sCr), blood urea nitrogen (BUN) and apoptosis of tubular cells were significantly increased in WT mice. However, Tisp40 deficiency significantly attenuated the increase of sCr, BUN and apoptosis of tubular cells. Following HR, apoptosis of tubular cells was increased in Tisp40 overexpression cells compared with vector cells. Mechanistically, Tisp40 promoted the expressions of C/EBP homologous protein (CHOP), Bax and Cleaved caspase3 and suppressed the expression of Bcl-2 in renal IR injury. In conclusion, Tisp40 aggravates tubular cells apoptosis in renal IR injury. [ABSTRACT FROM AUTHOR]

Renal ischemia-reperfusion (IR) contributes to the development of acute renal failure (ARF). Oxygen free radicals are considered to be principal components involved in the pathophysiological tissue alterations observed during renal IR. The purpose of this study was to investigate the combination effect of melatonin (MEL) and erythropoietin (EPO), which are a potent antioxidant and anti-apoptotic agents, in IR-induced renal injury in rats. Wistar Albino rats were unilaterally nephrectomized and subjected to 45 min of renal pedicle occlusion followed by 24 h reperfusion. MEL (10 mg/kg, i.p) and EPO (5000 U/kg, i.p) were administered prior to ischemia. After 24 h reperfusion, following decapitation, blood samples were collected for the determination of superoxide dismutase (SOD), glutathione peroxidase (GPx), and malondialdehyde (MDA) levels. Also, renal samples were taken for histological evaluation and apoptosis assay. Ischemia-reperfusion increased SOD, GPx, MDA levels, and TUNEL positive cells. Histopathological findings of the IR group confirmed that there was renal impairment in the tubular epithelium. Treatment with EPO and MEL decreased SOD, GPx, and MDA levels, histopathological changes, and TUNEL positive cells. These results indicated that the combination of MEL and EPO could not exert more nephroprotective and anti-apoptotic effects than MEL treatment in renal ischemia-reperfusion injury.