scholarly journals Netrin-1 and kidney injury. I. Netrin-1 protects against ischemia-reperfusion injury of the kidney

2008 ◽  
Vol 294 (4) ◽  
pp. F739-F747 ◽  
Author(s):  
Weiwei Wang ◽  
W. Brian Reeves ◽  
Ganesan Ramesh
Keyword(s):  
Cell Activation ◽  
Ischemia Reperfusion Injury ◽  
Vascular Endothelial Cells ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Tubular Damage ◽  
Endothelial Cell Activation ◽  
Protein Levels ◽  
Peritubular Capillaries ◽  
The Impact

Endogenous mechanisms exist to limit inflammation. One such molecule is netrin. This study examined the impact of ischemia-reperfusion (I/R) on netrin expression and the role of netrin in preventing renal inflammation and injury. All three isoforms of netrin (1, 3, and 4) are expressed in normal kidney. I/R significantly downregulated netrin-1 and -4 mRNA expression, whereas expression of netrin-3 was moderately upregulated at 24 h of reperfusion. The netrin receptor UNC5B mRNA increased at 3 h and but decreased at later time points. Expression of a second netrin receptor, DCC, was not altered significantly. I/R was associated with dramatic changes in netrin-1 protein abundance and localization. Netrin-1 protein levels increased between 3 and 24 h after reperfusion. Immunolocalization showed an interstitial distribution of netrin-1 in sham-operated kidneys which colocalized with Von Willebrand Factor suggesting the presence of netrin-1 in peritubular capillaries. After I/R, interstitial netrin-1 expression decreased and netrin-1 appeared in tubular epithelial cells. By 72 h after reperfusion, netrin-1 reappeared in the interstitium while tubular epithelial staining decreased significantly. Downregulation of netrin-1 in the interstitium corresponded with increased MCP-1 and IL-6 expression and infiltration of leukocytes into the reperfused kidney. Administration of recombinant netrin-1 significantly improved kidney function (blood urea nitrogen: 161 ± 7 vs. 104 ± 24 mg/dl, creatinine: 1.3 ± 0.07 vs. 0.75 ± 0.16 mg/dl, P < 0.05 at 24 h) and reduced tubular damage and leukocyte infiltration in the outer medulla. These results suggest that downregulation of netrin-1 in vascular endothelial cells may promote endothelial cell activation and infiltration of leukocytes into the kidney thereby enhancing tubular injury.

Antibiotic-induced microbiome depletion alters renal glucose metabolism and exacerbates renal injury after ischemia-reperfusion injury in mice

2021 ◽  
Author(s):  
Yuika Osada ◽  
Shunsaku Nakagawa ◽  
Kanako Ishibe ◽  
Shota Takao ◽  
Aimi Shimazaki ◽  
...  
Keyword(s):  
Glucose Metabolism ◽  
Glucose Homeostasis ◽  
Phosphoenolpyruvate Carboxykinase ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Critical Role ◽  
Kidney Injury ◽  
Short Chain Fatty Acids ◽  
Glucose Levels ◽  
The Impact

Recent studies have revealed the impact of antibiotic-induced microbiome depletion (AIMD) on host glucose homeostasis. The kidney has a critical role in systemic glucose homeostasis; however, information regarding the association between AIMD and renal glucose metabolism remains limited. Hence, we aimed to determine the effects of AIMD on renal glucose metabolism by inducing gut microbiome depletion using an antibiotic cocktail (ABX) composed of ampicillin, vancomycin, and levofloxacin in mice. The results showed that the bacterial 16s rRNA expression, luminal concentrations of short-chain fatty acids and bile acids, and plasma glucose levels were significantly lower in ABX-treated mice than in vehicle-treated mice. In addition, ABX treatment significantly reduced renal glucose and pyruvate levels. The mRNA expression levels of glucose-6-phosphatase and phosphoenolpyruvate carboxykinase in the renal cortex were significantly higher in ABX-treated mice than in vehicle-treated mice. We further examined the impact of AIMD on the altered metabolic status in mice after ischemia-induced kidney injury. After exposure to ischemia for 60 min, the renal pyruvate concentrations were significantly lower in ABX-treated mice than in vehicle-treated mice. ABX treatment caused a more severe tubular injury after ischemia-reperfusion (IR). Our findings confirm that AIMD is associated with decreased pyruvate levels in the kidney, which may have been caused by the activation of renal gluconeogenesis. Thus, we hypothesized that AIMD would increase the vulnerability of the kidney to IR injury.

scholarly journals Arginase-2 mediates renal ischemia-reperfusion injury

2017 ◽  
Vol 313 (2) ◽  
pp. F522-F534 ◽  
Author(s):  
Wesley M. Raup-Konsavage ◽  
Ting Gao ◽  
Timothy K. Cooper ◽  
Sidney M. Morris ◽  
W. Brian Reeves ◽  
...  
Keyword(s):  
Reperfusion Injury ◽  
Blood Urea Nitrogen ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Renal Ischemia ◽  
Arginase Activity ◽  
Urea Nitrogen ◽  
The Impact ◽  
Novel Therapeutic

Novel therapeutic interventions for preventing or attenuating kidney injury following ischemia-reperfusion injury (IRI) remain a focus of significant interest. Currently, there are no definitive therapeutic or preventive approaches available for ischemic acute kidney injury (AKI). Our objective is to determine 1) whether renal arginase activity or expression is increased in renal IRI, and 2) whether arginase plays a role in development of renal IRI. The impact of arginase activity and expression on renal damage was evaluated in male C57BL/6J (wild type) and arginase-2 (ARG2)-deficient ( Arg2−/−) mice subjected to bilateral renal ischemia for 28 min, followed by reperfusion for 24 h. ARG2 expression and arginase activity significantly increased following renal IRI, paralleling the increase in kidney injury. Pharmacological blockade or genetic deficiency of Arg2 conferred kidney protection in renal IRI. Arg2−/− mice had significantly attenuated kidney injury and lower plasma creatinine and blood urea nitrogen levels after renal IRI. Blocking arginases using S-(2-boronoethyl)-l-cysteine (BEC) 18 h before ischemia mimicked arginase deficiency by reducing kidney injury, histopathological changes and kidney injury marker-1 expression, renal apoptosis, kidney inflammatory cell recruitment and inflammatory cytokines, and kidney oxidative stress; increasing kidney nitric oxide (NO) production and endothelial NO synthase (eNOS) phosphorylation, kidney peroxisome proliferator-activated receptor-γ coactivator-1α expression, and mitochondrial ATP; and preserving kidney mitochondrial ultrastructure compared with vehicle-treated IRI mice. Importantly, BEC-treated eNOS-knockout mice failed to reduce blood urea nitrogen and creatinine following renal IRI. These findings indicate that ARG2 plays a major role in renal IRI, via an eNOS-dependent mechanism, and that blocking ARG2 activity or expression could be a novel therapeutic approach for prevention of AKI.

scholarly journals Endothelial Cell Activation in an Embolic Ischemia-Reperfusion Injury Microfluidic Model

Micromachines ◽  
2019 ◽  
Vol 10 (12) ◽  
pp. 857 ◽  
Author(s):  
Danielle Nemcovsky Amar ◽  
Mark Epshtein ◽  
Netanel Korin
Keyword(s):  
Endothelial Cells ◽  
Endothelial Cell ◽  
Reperfusion Injury ◽  
Cell Activation ◽  
Ischemia Reperfusion Injury ◽  
Blood Clot ◽  
Ischemia Reperfusion ◽  
Clot Lysis ◽  
Endothelial Cell Activation ◽  
Myocardial Infraction

Ischemia, lack of blood supply, is associated with a variety of life-threatening cardiovascular diseases, including acute ischemic stroke and myocardial infraction. While blood flow restoration is critical to prevent further damage, paradoxically, rapid reperfusion can increase tissue damage. A variety of animal models have been developed to investigate ischemia/reperfusion injury (IRI), however they do not fully recapitulate human physiology of IRI. Here, we present a microfluidic IRI model utilizing a vascular compartment comprising human endothelial cells, which can be obstructed via a human blood clot and then re-perfused via thrombolytic treatment. Using our model, a significant increase in the expression of the endothelial cell inflammatory surface receptors E-selectin and I-CAM1 was observed in response to embolic occlusion. Following the demonstration of clot lysis and reperfusion via treatment using a thrombolytic agent, a significant decrease in the number of adherent endothelial cells and an increase in I-CAM1 levels compared to embolic occluded models, where reperfusion was not established, was observed. Altogether, the presented model can be applied to allow better understanding of human embolic based IRI and potentially serve as a platform for the development of improved and new therapeutic approaches.

scholarly journals No Signs of Inflammation during Knee Surgery with Ischemia: A Study Involving Inhaled Nitric Oxide

2014 ◽  
Vol 2014 ◽  
pp. 1-8 ◽  
Author(s):  
Lars Hållström ◽  
Claes Frostell ◽  
Anders Herrlin ◽  
Eva Lindroos ◽  
Ingrid Lundberg ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Inflammatory Response ◽  
Reperfusion Injury ◽  
Cell Activation ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Inhaled Nitric Oxide ◽  
Endothelial Cell Activation ◽  
Soluble Adhesion Molecules ◽  
Group 2

Nitric oxide donors and inhaled nitric oxide (iNO) may decrease ischemia/reperfusion injury as reported in animal and human models. We investigated whether the attenuation of reperfusion injury, seen by others, in patients undergoing knee arthroplasty could be reproduced when patients had spinal anesthesia. 45 consecutive patients were randomized into three groups (n=15). Groups 1 and 3 were receiving iNO 80 ppm or placebo (nitrogen, N2) throughout the entire operation, and group 2 only received iNO in the beginning and at the end of the operation. Blood samples were collected before surgery, at the end of the surgery, and 2 hours postoperatively. Muscle biopsies were taken from quadriceps femoris muscle before and after ischemia. There were no increases in plasma levels of soluble adhesion molecules: ICAM, VCAM, P-selectin, E-selectin, or of HMGB1, in any of the groups. There were low numbers of CD68+ macrophages and of endothelial cells expression of ICAM, VCAM, and P-selectin in the muscle analyzed by immunohistochemistry, prior to and after ischemia. No signs of endothelial cell activation or inflammatory response neither systemically nor locally could be detected. The absence of inflammatory response questions this model of ischemia/reperfusion, but may also be related to the choice of anesthetic method EudraCTnr.

scholarly journals Effects of C1 inhibitor on endothelial cell activation in a rat hind limb ischemia-reperfusion injury model

2018 ◽  
Vol 68 (6) ◽  
pp. 209S-221S.e2 ◽  
Author(s):  
Shengye Zhang ◽  
Jane Shaw-Boden ◽  
Yara Banz ◽  
Anjan K. Bongoni ◽  
Adriano Taddeo ◽  
...  
Keyword(s):  
Endothelial Cell ◽  
Reperfusion Injury ◽  
Hind Limb ◽  
Cell Activation ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Limb Ischemia ◽  
C1 Inhibitor ◽  
Endothelial Cell Activation ◽  
Injury Model

scholarly journals Genetic Deletion of Vasohibin-2 Exacerbates Ischemia-Reperfusion-Induced Acute Kidney Injury

2020 ◽  
Vol 21 (12) ◽  
pp. 4545 ◽  
Author(s):  
Hiromasa Miyake ◽  
Katsuyuki Tanabe ◽  
Satoshi Tanimura ◽  
Yuri Nakashima ◽  
Tomoyo Morioka ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Kidney Diseases ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Neutrophil Infiltration ◽  
Endothelial Damage ◽  
Tubular Damage ◽  
Renal Tubules ◽  
Inflammatory Infiltration ◽  
Peritubular Capillaries

Acute kidney injury (AKI) has been increasingly recognized as a risk factor for transition to chronic kidney disease. Recent evidence suggests that endothelial damage in peritubular capillaries can accelerate the progression of renal injury. Vasohibin-2 (VASH2) is a novel proangiogenic factor that promotes tumor angiogenesis. However, the pathophysiological roles of VASH2 in kidney diseases remain unknown. In the present study, we examined the effects of VASH2 deficiency on the progression of ischemia–reperfusion (I/R) injury-induced AKI. I/R injury was induced by bilaterally clamping renal pedicles for 25 min in male wild-type (WT) and Vash2 homozygous knockout mice. Twenty-four hours later, I/R injury-induced renal dysfunction and tubular damage were more severe in VASH2-deficient mice than in WT mice, with more prominent neutrophil infiltration and peritubular capillary loss. After induction of I/R injury, VASH2 expression was markedly increased in injured renal tubules. These results suggest that VASH2 expression in renal tubular epithelial cells might be essential for alleviating I/R injury-induced AKI, probably through protecting peritubular capillaries and preventing inflammatory infiltration.

Discovery, in-vitro and in-vivo efficacy of an anti-inflammatory small molecule inhibitor of C-reactive protein

2021 ◽  
Author(s):  
Johannes Zeller ◽  
Karen Cheung Tung Shing ◽  
Tracy Nero ◽  
Guy Krippner ◽  
James McFadyen ◽  
...  
Keyword(s):  
Cell Activation ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Acute Ischemia ◽  
C Reactive Protein ◽  
Endothelial Cell Activation ◽  
Reactive Protein ◽  
Anti Inflammatory

Abstract C-reactive protein (CRP) is an acute phase protein. We recently identified a novel mechanism that leads to a conformational change from the native, pentameric structure (pCRP) to a pentameric intermediate (pCRP*) and ultimately to the monomeric form, mCRP, both being highly pro-inflammatory. This ‘CRP activation’ is mediated by binding of pCRP to activated/damaged cell membranes via exposed phosphocholine (PC) lipid head groups. We designed a low molecular weight pCRP – PC inhibitor, C10M. Binding assays and X-ray crystallography revealed direct, competitive binding of C10M to pCRP, blocking interaction with PC and thereby inhibiting formation of pCRP*/mCRP and their pro-inflammatory effects. The anti-inflammatory potential of C10M was confirmed in-vitro by various measures of leukocyte and endothelial cell activation and in-vivo in rat models of acute ischemia/reperfusion injury and hindlimb transplantation. In conclusion, inhibition of pCRP*/mCRP generation via the PC-mimicking compound C10M represents a promising, potentially broadly applicable anti-inflammatory therapy.

scholarly journals Dual role of protease activated receptor 4 in acute kidney injury: contributing to renal injury and inflammation, while maintaining the renal filtration barrier upon acute renal ischemia reperfusion injury

2019 ◽  
Author(s):  
Marcel. P. B. Jansen ◽  
Nike Claessen ◽  
Per W.B. Larsen ◽  
Loes M. Butter ◽  
Sandrine Florquin ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Renal Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Neutrophil Migration ◽  
Kidney Injury ◽  
Protease Activated Receptors ◽  
Filtration Barrier ◽  
Peritubular Capillaries ◽  
Acute Renal Ischemia

AbstractIschemia reperfusion (I/R) injury triggers the activation of coagulation and inflammation processes involved in the pathophysiology of acute kidney injury (AKI). Coagulation proteases upregulated upon renal I/R injury activate protease activated receptors (PARs), which form an important molecular link between inflammation and coagulation. PAR4 is the major thrombin receptor on mouse platelets, and the only PAR that is expressed on both human and murine platelets. In addition, PAR4 is expressed on other cells including podocytes. We here sought to determine the contribution of PAR4 in the host response to renal I/R injury. Hence, we subjected PAR4 knockout and wild-type mice to renal I/R injury. PAR4 knockout mice exhibited an increased tolerance to renal tubular necrosis and showed a decreased neutrophil influx in response to renal I/R, independent from platelet PAR4. On the other hand, PAR4 deficiency resulted in albumin cast formation in peritubular capillaries and showed a tendency towards albuminuria. Transmission Electron Microscopy revealed an increase in podocyte foot process effacement. Our findings suggest that PAR4 contributes to renal injury likely through facilitating neutrophil migration, independent from platelet PAR4. In addition, PAR4 fulfils an important function in the maintenance of podocyte integrity following renal I/R insult. Subsequently, loss of PAR4 results in albuminuria.

scholarly journals Ischemic Postconditioning and Subanesthetic S(+)-Ketamine Infusion: Effects on Renal Function and Histology in Rats

2015 ◽  
Vol 2015 ◽  
pp. 1-8 ◽  
Author(s):  
Marco A. C. de Resende ◽  
Alberto V. Pantoja ◽  
Bruno M. Barcellos ◽  
Eduardo P. Reis ◽  
Thays D. Consolo ◽  
...  
Keyword(s):  
Renal Function ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Left Kidney ◽  
Arterial Occlusion ◽  
Kidney Injury ◽  
Ischemic Postconditioning ◽  
Tubular Damage ◽  
Ketamine Infusion ◽  
Renal Histology

Background. Ischemic postconditioning (IP) in renal Ischemia reperfusion injury (IRI) models improves renal function after IRI. Ketamine affords significant benefits against IRI-induced acute kidney injury (AKI). The present study investigated the effects of IP and IP associated with subanesthetic S(+)-ketamine in ischemia-reperfusion-induced AKI.Methods. Forty-one Wistar rats were randomized into four groups: CG (10), control; KG (10), S(+)-ketamine infusion; IPG (10), IP; and KIPG (11), S(+)-ketamine infusion + IP. All rats underwent right nephrectomy. IRI and IP were induced only in IPG and KIPG by left kidney arterial occlusion for 30 min followed by reperfusion for 24 h. Complete reperfusion was preceded by three cycles of 2 min of reocclusion followed by 2 min of reperfusion. Renal function was assessed by measuring serum neutrophil gelatinase-associated lipocalin (NGAL), creatinine, and blood urea nitrogen (BUN). Tubular damage was evaluated by renal histology.Results. Creatinine and BUN were significantly increased. Severe tubular injury was only observed in the groups with IRI (IPG and KIPG), whereas no injury was observed in CG or KG. No significant differences were detected between IPG and KIPG.Conclusions. No synergic effect of the use of subanesthetic S(+)-ketamine and IP on AKI was observed in this rat model.

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