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Renal ischemia/reperfusion (I/R) injury is a common clinical challenge faced by clinicians in kidney transplantation. I/R is the leading cause of acute kidney injury, and it occurs when blood flow to the kidney is interrupted and subsequently restored. I/R impairs renal function in both short and long terms. Renal ischemic preconditioning refers to all maneuvers intended to prevent or attenuate ischemic damage. In this context, the present review focuses on the dual-specificity phosphatase 3 (DUSP3), also known as vaccinia H1-related phosphatase, an uncommon regulator of mitogen-activated protein kinase (MAPK) phosphorylation. DUSP3 has different biological functions: (1) it acts as a tumor modulator and (2) it is involved in the regulation of immune response, thrombosis, hemostasis, angiogenesis, and genomic stability. These functions occur either through MAPK-dependent or MAPK-independent mechanisms. DUSP3 genetic deletion dampens kidney damage and inflammation caused by I/R in mice, suggesting DUSP3 as a potential target for preventing renal I/R injury. Here, we discuss the putative role of DUSP3 in ischemic preconditioning and the potential mechanisms of such an attenuated inflammatory response via improved kidney perfusion and adequate innate immune response., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background/aim: Acute and chronic kidney diseases are a major contributor to morbidity and mortality worldwide, with no specific treatments currently available for these. To enable understanding the pathophysiology of and testing novel treatments for acute and chronic kidney disease, a suitable in vivo model of kidney disease is essential. In this article, we describe two reliable rodent models (rats and mice) of efficacious kidney injury displaying acute to chronic kidney injury progression, which is also reversible through novel therapeutic strategies such as ischemic preconditioning (IPC)., Materials and Methods: We utilized adult male Lewis rats and adult male wildtype (C57BL/6) mice, performed a midline laparotomy, and induced warm ischemia to both kidneys by bilateral clamping of both renal vascular pedicles for a set time, to mimic the hypoxic etiology of disease commonly found in kidney injury., Results: Bilateral ischemia reperfusion injury caused marked structural and functional kidney injury as exemplified by histology damage scores, serum creatinine levels, and kidney injury biomarker levels in both rodents. Furthermore, this effect displayed a dose-dependent response in the mouse model., Conclusion: These rodent models of bilateral kidney IRI are reliable, reproducible, and enable detailed mechanistic study of the underlying pathophysiology of both acute and chronic kidney disease. They have been carefully optimised for single operator use with a strong track record of training both surgically trained and surgically naïve operators., (Copyright © 2024, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Lesions issued from the ischemia/reperfusion (I/R) stress are a major challenge in human pathophysiology. Of human organs, the kidney is highly sensitive to I/R because of its high oxygen demand and poor regenerative capacity. Previous studies have shown that targeting the hypusination pathway of eIF5A through GC7 greatly improves ischemic tolerance and can be applied successfully to kidney transplants. The protection process correlates with a metabolic shift from oxidative phosphorylation to glycolysis. Because the protein kinase B Akt is involved in ischemic protective mechanisms and glucose metabolism, we looked for a link between the effects of GC7 and Akt in proximal kidney cells exposed to anoxia or the mitotoxic myxothiazol. We found that GC7 treatment resulted in impaired Akt phosphorylation at the Ser473 and Thr308 sites, so the effects of direct Akt inhibition as a preconditioning protocol on ischemic tolerance were investigated. We evidenced that Akt inhibitors provide huge protection for kidney cells against ischemia and myxothiazol. The pro-survival effect of Akt inhibitors, which is reversible, implied a decrease in mitochondrial ROS production but was not related to metabolic changes or an antioxidant defense increase. Therefore, the inhibition of Akt can be considered as a preconditioning treatment against ischemia.

Background: To investigate if remote ischemic preconditioning (RIPC) can offer any renoprotective value by counteracting the deleterious effect of partial nephrectomy (PN) under warm ischemia on renal function., Methods: Four groups, each with 5 Wistar albino rats, were constructed; RIPC + PN, PN, RIPC and sham. Right nephrectomy was performed to constitute a solitary kidney model. RIPC denoted sequential clamping/declamping of the femoral artery/vein complex. PN was performed under warm-ischemia following RIPC. Blood samples were collected on multiple occasions until euthanasia on day 7. Immunoassays were conducted to measure the serum and tissues levels of kidney injury markers. Kidneys were examined histologically and morphometric analyzes were performed using digital scanning., Results: IL-33 levels did not differ significantly between the groups. Serum levels of KIM-1, NGAL, and aldose reductase in RIPC + PN, PN and RIPC groups were significantly lower than that of sham group. Tissue biomarker levels were similar across groups. The observed trend in mean necrosis area of PN group was higher than that of RIPC + PN group (p > 0.05). The transitional zone between necrosis and healthy tissue showed a trend towards increasing width in the rats subjected to RIPC before PN vs. those who underwent PN without RIPC (p > 0.05)., Conclusion: RIPC failed to counteract the renal functional consequences of PN under warm ischemia in a solitary kidney animal model. The supportive but marginal histological findings in favor of RIPC's renoprotective potential were not supplemented with the changes in serum and tissue biomarker levels., (© 2021. The Author(s).)

In the perioperative setting, acute kidney injury (AKI) is a frequent complication, and AKI itself is associated with adverse outcomes such as higher risk of chronic kidney disease and mortality. Various risk factors are associated with perioperative AKI, and identifying them is crucial to early interventions addressing modifiable risk and increasing monitoring for nonmodifiable risk. Different mechanisms are involved in the development of postoperative AKI, frequently picturing a multifactorial etiology. For these reasons, no single renoprotective strategy will be effective for all surgical patients, and efforts have been attempted to prevent kidney injury in different ways. Some renoprotective strategies and treatments have proven to be useful, some are no longer recommended because they are ineffective or even harmful, and some strategies are still under investigation to identify the best timing, setting, and patients for whom they could be beneficial. With this review, we aim to provide an overview of recent findings from studies examining epidemiology, risk factors, and mechanisms of perioperative AKI, as well as different renoprotective strategies and treatments presented in the literature.

Acute kidney injury (AKI) is one of the most common and troublesome perioperative complications. Dexmedetomidine (DEX) is a potent α 2-adrenoceptor ( α 2-AR) agonist with anti-inflammatory and renoprotective effects. In this study, a rat renal ischemia-reperfusion injury (IRI) model was induced. At 24 h after reperfusion, the IRI-induced damage and the renoprotection of DEX preconditioning were confirmed both biochemically and histologically. Changes in nuclear factor-kappa B (NF- κ B), as well as its downstream anti-inflammatory factor A20 and proinflammatory factor tumor necrosis factor- α (TNF- α ), were detected. Atipamezole, a nonselective antagonist, was then added 5 min before the administration of DEX to further analyze DEX's effects on NF- κ B, and another anti-inflammatory medicine, methylprednisolone, was used in comparison with DEX, to further analyze DEX's effects on NF- κ B. Different concentrations of DEX (0 nM, 0.1 nM, 1 nM, 10 nM, 100 nM, 1  μ M, and 10  μ M) were applied to preincubated human renal tubular epithelial cell line (HK-2) cells in vitro. After anoxia and reoxygenation, the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) tetrazolium assay and enzyme-linked immunosorbent assay (ELISA) were performed to evaluate the levels of NF- κ B downstream anti-inflammatory cytokines. The results showed that, unlike methylprednisolone, DEX preconditioning led to a time-dependent biphasic change (first activation then inhibition) of NF- κ B in the rat renal IRI models that were given 25  μ g/kg i.p. It was accompanied by a similarly biphasic change of TNF- α and an early and persistent upregulation of A20. In vitro, DEX's cellular protection showed a concentration-dependent biphasic change which was protective within the range of 0 to 100 nM but became opposite when concentrations are greater than 1  μ M. The changes in the A20 and NF- κ B messenger RNA (mRNA) levels were consistent with the renoprotective ability of DEX. In other words, DEX preconditioning protected the rats from renal IRI via regulation biphasic change of NF- κ B signaling., Competing Interests: The authors of this manuscript declare there is no conflict of interest., (Copyright © 2020 Naren Bao et al.)

Purpose: Contrast-induced acute kidney injury (CI-AKI) resulting from administration of iodinated contrast media (CM) is the third leading cause of hospital-acquired acute kidney injury and is associated with substantial morbidity and mortality. Deteriorated renal microcirculation plays an important role in CI-AKI. Limb ischemic preconditioning (LIPC), where brief and non-injurious ischemia/reperfusion is applied to a limb prior to the administration of the contrast agent, is emerging as a promising strategy for CI-AKI prevention. However, it is not known whether the renal protection of LIPC against CI-AKI is mediated by regulation of renal microcirculation and the molecular mechanisms remain largely unknown., Methods: In this study, we examined the renal cortical and medullary blood flow in a stable CI-AKI model using 5/6-nephrectomized (NE) rat. The LIPC and sham procedures were performed prior to the injection of CM. Furthermore, we analyzed renal medulla hypoxia using in vivo labeling of hypoxyprobe. Pharmacological inhibitions and western blotting were used to determine the underlying molecular mechanisms., Results: In this study, we found LIPC significantly ameliorated CM-induced reduction of medullary blood flow and attenuated CM-induced hypoxia. PI3K inhibitor (wortmannin) treatment blocked the regulation of medullary blood flow and the attenuation of hypoxia of LIPC. Phosphorylation of Akt/eNOS was significantly decreased via wortmannin treatment compared with LIPC. Nitric oxide synthase-inhibitor [Nω-nitro-L-arginine methyl ester (L-NAME)] treatment abolished the above effects and decreased phosphorylation of eNOS, but not Akt., Conclusions: Collectively, the results demonstrate that LIPC ameliorates CM-induced renal vasocontraction and is mediated by activation of PI3K/Akt/eNOS signaling pathway.

Background and Aims: Perioperative kidney injury affects 12.7% of patients undergoing lower limb revascularisation surgery. Remote ischaemic preconditioning (RIPC) is a potentially protective procedure against organ damage and consists of short nonlethal episodes of ischaemia. The main objective of this substudy was to evaluate the effect of RIPC on kidney function, inflammation, and oxidative stress in patients undergoing open surgical lower limb revascularisation. Materials and Methods . This is a subgroup analysis of a randomised, sham-controlled, double-blinded, single-centre study. A RIPC or a sham procedure was performed noninvasively along with preparation for anaesthesia in patients undergoing open surgical lower limb revascularisation. The RIPC protocol consisted of 4 cycles of 5 minutes of ischaemia, with 5 minutes of reperfusion between every episode. Blood was collected for analysis preoperatively, 2, 8, and 24 hours after surgery, and urine was collected preoperatively and 24 hours after surgery., Results: Data of 56 patients were included in the analysis. Serum creatinine, cystatin C, and beta-2 microglobulin increased, and eGFR decreased across all time points significantly more in the sham group than in the RIPC group ( p = 0.021, p = 0.021, p = 0.021, p = 0.021, p = 0.021., Conclusions: Our finding of reduced release of kidney injury biomarkers may indicate the renoprotective effect of RIPC in patients undergoing open surgical lower limb revascularisation. The trial is registered with ClinicalTrials.gov NCT02689414., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2020 Teele Kasepalu et al.)

Background: The optimal timing of remote ischemic preconditioning (RIPC) in renal ischemia-reperfusion (I/R) injury is still unclear. We aimed to compare early- and delayed-effect RIPC with hematological, microcirculatory and histomorphological parameters., Methods: In anesthetized male CrI:WI Control rats (n = 7) laparotomy and femoral artery cannulation were performed. In I/R group (n = 7) additionally a 45-minute unilateral renal ischemia with 120-minute reperfusion was induced. The right hind-limb was strangulated for 3×10 minutes (10-minute intermittent reperfusion) 1 hour (RIPC-1 group, n = 7) or 24 hour (RIPC-24 group, n = 6) prior to the I/R. Hemodynamic, hematological parameters and organs' surface microcirculation were measured., Results: Control and I/R group had the highest heart rate (p < 0.05 vs base), while the lowest mean arterial pressure (p < 0.05 vs RIPC-1) were found in the RIPC-24 group. The highest microcirculation values were measured in the I/R group (liver: p < 0.05 vs Control). The leukocyte count increased in I/R group (base: p < 0.05 vs Control), also this group's histological score was the highest (p < 0.05 vs Control). The RIPC-24 group had a significantly lower score than the RIPC-1 (p = 0.0025 vs RIPC-1)., Conclusion: Renal I/R caused significant functional and morphological, also in the RIPC groups. According to the histological examination the delayed-effect RIPC method was more effective.

Background: Acute kidney injury (AKI) as a consequence of ischemia is a common clinical event that can lead to unacceptably high morbidity and mortality. Hyperbaric oxygen (HBO2) preconditioning has been shown to prevent ischemia-reperfusion injury (IRI) in different tissues., Objectives: The aim of our study was to compare the effects of HBO2 preconditioning on renal hemodynamics, kidney function and oxidative stress in normotensive and spontaneously hypertensive rats that suffered kidney IRI., Methods: An experiment was performed on Wistar (normotensive) and spontaneously hypertensive rats (SHR). The animals were divided into the following experimental groups: sham-operated rats and rats with or without HBO2 preconditioning 24 hours before post-ischemic AKI induction. Treated rats were placed into experimental HBO2 chambers and exposed to pure oxygen twice a day for two consecutive days (2.026 bar of oxygen) for 60 minutes. AKI was performed the next morning. The right kidney was removed and the renal ischemia was performed by clamping the left renal artery for 45 minutes., Results: In this study, HBO2 preconditioning significantly improved disturbed renal hemodynamics, major markers of kidney function in plasma (creatinine, urea and phosphate) as well as antioxidant enzymes (superoxide dismutase and catalase) activities in erythrocytes after AKI induction. Also, HBO2 preconditioning decreased lipid peroxidation in plasma after ischemic AKI. Positive effects were observed in both strains of rats., Conclusions: Our results suggest that HBO2 treatment improves renal hemodynamic and kidney function and decreases oxidative stress of Wistar and SHR rats with an AKI episode. Furthermore, it also implies that pre-existing hypertension does not affect the beneficial effects of HBO2 preconditioning., Competing Interests: The authors of this paper declare no conflicts of interest exist with this submission., (Copyright© Undersea and Hyperbaric Medical Society.)

Purpose: To determine the role of remote perconditioning (RPeC) on renal function and histology in an animal model of unilateral renal ischemia and reperfusion (IR) injury., Methods: Rats were subjected to 60 min unilateral renal ischemia. RPeC protocol was the application of four cycles of 5 min IR of left femoral artery during renal ischemia. Assessments of histological changes and renal function were made 24 h, 1 week, or 3 weeks later. 99mTc-DMSA scan was performed using a small-animals SPECT system., Results: 24-h reperfusion decreased the 99mTc-DMSA uptake in the left kidney compared to the intact kidney of control animals. RPeC group has higher uptake compared to the IR group. After 1 week and 3 weeks, uptakes were gradually increased in both groups and no differences were observed. Severe morphological changes in the ischemic kidneys of both groups were observed after 24 h which attenuated after 1 week and 3 weeks. Moreover, no differences in creatinine and BUN levels between IR-treated and intact animals were observed., Conclusion: These data suggest that RPeC exerts a partially transient improvement in the renal function in the first day after reperfusion. However, long-term follow-up study showed no beneficial effects of RPeC. Moreover, noninvasive 99mTc-DMSA scan revealed a suitable tool in the follow-up evaluation of recovery process in the unilateral renal IR injury models.

Although kidney oxygen tensions are heterogenous, and mostly below renal vein level, the nephron is highly dependent on aerobic metabolism for active tubular transport. This renders the kidney particularly susceptible to hypoxia, which is considered a main characteristic and driver of acute and chronic kidney injury, albeit the evidence supporting this assumption is not entirely conclusive. Kidney transplants are exposed to several conditions that may interfere with the balance between oxygen supply and consumption, and enhance hypoxia and hypoxic injury. These include conditions leading to and resulting from brain death of kidney donors, ischemia and reperfusion during organ donation, storage and transplantation, postoperative vascular complications, vasoconstriction induced by immunosuppression, and impaired perfusion resulting from interstitial edema, inflammation, and fibrosis. Acute graft injury, the immediate consequence of hypoxia and reperfusion, results in delayed graft function and increased risk of chronic graft failure. Although current strategies to alleviate hypoxic/ischemic graft injury focus on limiting injury (eg, by reducing cold and warm ischemia times), experimental evidence suggests that preconditioning through local or remote ischemia, or activation of the hypoxia-inducible factor pathway, can decrease hypoxic injury. In combination with ex vivo machine perfusion such approaches hold significant promise for improving transplantation outcomes., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Kidneys have an important role in regulating water volume, blood pressure, secretion of hormones and acid-base and electrolyte balance. Kidney dysfunction derived from acute injury can, under certain conditions, progress to chronic kidney disease. In the late stages of kidney disease, treatment is limited to replacement therapy: Dialysis and transplantation. After renal transplant, grafts suffer from activation of immune cells and generation of oxidant molecules. Anesthetic preconditioning has emerged as a promising strategy to ameliorate ischemia reperfusion injury. This review compiles some significant aspects of renal physiology and discusses current understanding of the effects of anesthetic preconditioning upon renal function and ischemia reperfusion injury, focusing on opioids and its properties ameliorating renal injury. According to the available evidence, opioid preconditioning appears to reduce inflammation and reactive oxygen species generation after ischemia reperfusion. Therefore, opioid preconditioning represents a promising strategy to reduce renal ischemia reperfusion injury and, its application on current clinical practice could be beneficial in events such as acute renal injury and kidney transplantation.

Background/aim: Since the nature of ischemia/reperfusion (IR)-induced tissue damage is multifactorial and complex, in the current study, the effects of multiple treatment strategies via concomitant administration of erythropoietin (EPO) and N-acetylcysteine (NAC) with an ischemic preconditioning (IPC) regimen on renal IR injury were examined., Materials and Methods: Thirty male Wistar rats were subjected to bilateral occlusion of the renal pedicles for 50 min followed by reperfusion. EPO (1000 IU/kg) was administered for 3 days, as well as IPC before the IR and NAC (150 mg/kg) administration for 4 days after IR. The animals were randomly allocated into 6 groups (n = 5): sham, IR, EPO+IR, IPC+IR, NAC+IR, and EPO+IPC+NAC+IR. Kidney tissues and blood samples were obtained for oxidative stress, proinflammatory cytokines, and renal functional evaluations., Results: IR caused significant inflammatory response, oxidative stress, and reduced renal function. Treatment with EPO, IPC, and NAC or a combination of two of them attenuated renal dysfunction and reduced the oxidative stress and inflammatory markers. Rats treated with the combination of EPO, IPC, and NAC showed a higher degree of protection compared to the other groups., Conclusion: These results showed that concomitant administration of EPO and IPC along with posttreatment NAC may have additive beneficial effects on kidney IR injury during IR-induced acute renal failure., (This work is licensed under a Creative Commons Attribution 4.0 International License)

Acute kidney injury (AKI) as a result of ischaemia-reperfusion represents a major healthcare burden worldwide. Mortality rates from AKI in hospitalized patients are extremely high and have changed little despite decades of research and medical advances. In 1986, Murry et al. demonstrated for the first time the phenomenon of ischaemic preconditioning to protect against ischaemia-reperfusion injury (IRI). This seminal finding paved the way for a broad body of research, which attempted to understand and ultimately harness this phenomenon for human application. The ability of preconditioning to limit renal IRI has now been demonstrated in multiple different animal models. However, more than 30 years later, a safe and consistent method of protecting human organs, including the kidneys, against IRI is still not available. This review highlights agents which, despite strong preclinical data, have recently failed to reduce AKI in human trials. The multiple reasons which may have contributed to the failure to translate some of the promising findings to clinical therapies are discussed. Agents which hold promise in the clinic because of their recent efficacy in preclinical large animal models are also reviewed.

Background: Acute kidney injury (AKI) may develop during partial nephrectomy due to ischemic reperfusion injury induced by renal artery clamping or surgical insult. The effect of remote ischemic preconditioning (RIPC) on reducing the renal injury after partial nephrectomy has not been evaluated in terms of urinary biomarkers., Methods/design: We will conduct a randomized controlled trial enrolling the patients who will undergo partial nephrectomy. In the study group, RIPC which consisted of four 5-min cycles of limb ischemia and reperfusion will be conducted after induction of anesthesia. Postoperative serum creatinine values, the incidence of AKI, and urinary biomarkers, including urinary creatinine, microalbumin, β-2 microglobulin, and N-acetyl-beta-D-glucosaminidase, will be compared between groups during the postoperative 2 weeks. Regional oxygen saturation on the skin of the contralateral kidney will be measured to evaluate the association between intraoperative regional oxygen saturation values and renal injury of the operating side., Discussion: We expect that our trial may demonstrate the effect of RIPC on mitigating the immediate postoperative renal injury and improving patient outcomes after partial nephrectomy. Moreover, our patients will undergo 99m Tc-DTPA radionuclide scintigraphy to calculate glomerular filtration rate 6 and 12 months after surgery. This data should show the long-term effect of RIPC., Trial Registration: ClinicalTrials.gov, ID: NCT03273751 . Registered on 6 September 2017.

Acute kidney injury (AKI) is a medical condition characterized by kidney damage with a rapid decline of renal function, which is associated with high mortality and morbidity. Recent research has further established an intimate relationship between AKI and chronic kidney disease. Perturbations of kidney cells in AKI result in the accumulation of unfolded and misfolded proteins in the endoplasmic reticulum (ER), leading to unfolded protein response (UPR) or ER stress. In this review, we analyze the role and regulation of ER stress in AKI triggered by renal ischemia-reperfusion and cisplatin nephrotoxicity. The balance between the two major components of UPR, the adaptive pathway and the apoptotic pathway, plays a critical role in determining the cell fate in ER stress. The adaptive pathway is evoked to attenuate translation, induce chaperones, maintain protein homeostasis and promote cell survival. Prolonged ER stress activates the apoptotic pathway, resulting in the elimination of dysfunctional cells. Therefore, regulating ER stress in kidney cells may provide a therapeutic target in AKI. KEY MESSAGES Perturbations of kidney cells in acute kidney injury result in the accumulation of unfolded and misfolded proteins in ER, leading to unfolded protein response (UPR) or ER stress. The balance between the adaptive pathway and the apoptotic pathway of UPR plays a critical role in determining the cell fate in ER stress. Modulation of ER stress in kidney cells may provide a therapeutic strategy for acute kidney injury.

Purpose: To evaluate whether combining hypothermia and remote ischemic preconditioning (RIPC) results in protection from ischemia-reperfusion (IR)., Methods: Thirty-two Wistar rats underwent right nephrectomy and were randomly assigned to four experimental protocols on the left kidney: warm ischemia (group 1), cold ischemia (group 2), RIPC followed by warm ischemia (group 3), and RIPC followed by cold ischemia (group 4). After 240 minutes of reperfusion, histological changes in the left kidney, as well as lipid peroxidation and antioxidant enzyme activity, were analyzed. The right kidney was used as the control. Serum creatinine was collected before and after the procedures., Results: RIPC combined with hypothermia during IR experiments revealed no differences on interventional groups regarding histological changes (p=0.722). Oxidative stress showed no significant variations among the groups. Lower serum creatinine at the end of the procedure was seen in animals exposed to hypothermia (p<0.001)., Conclusions: Combination of RIPC and local hypothermia provides no renal protection in IR injury. Hypothermia preserves renal function during ischemic events. Furthermore, RIPC followed by warm IR did not show benefits compared to warm IR alone or controls in our experimental protocol.

Contrast-induced nephropathy (CIN) is an important complication following diagnostic radiographic imaging and interventional therapy. It results from administration of intravascular iodinated contrast media (CM) and is currently the third most common cause of hospital-acquired acute kidney injury. CIN is associated with increased morbidity, prolonged hospitalization, and higher mortality. Although the importance of CIN is widely appreciated, and its occurrence can be mitigated by the use of pre- and posthydration protocols and low osmolar instead of high osmolar iodine-containing CM, specific prophylactic therapy is lacking. Remote ischemic preconditioning (RIPC), induced through short cycles of ischemia-reperfusion applied to the limb, is an intriguing new strategy that has been shown to reduce myocardial infarction size in patients undergoing emergency percutaneous coronary intervention. Furthermore, multiple proof-of-principle clinical studies have suggested benefit in several other ischemia-reperfusion syndromes, including stroke. Perhaps somewhat surprisingly, RIPC also is emerging as a promising strategy for CIN prevention. In this review, we discuss current clinical and experimental developments regarding the biology of CIN, concentrating on the pathophysiology of CIN, and cellular and molecular mechanisms by which limb ischemic preconditioning may confer renal protection in clinical and experimental models of CIN.

Background/aims: Even though delayed ischemic preconditioning (DIPC) has been reported to produce renal protection, the underlying mechanism remains poorly understood. We reported that a 15-minute renal ischemic preconditioning (IPC) 4 days before subsequent ischemia-reperfusion attenuated renal injury Kidney dendritic cells (DCs) are abundant in the renal tubulointerstitium and, depending on their status, can induce immune activation or tolerance. The aim of the present study was to investigate the role of DCs in IPC of the kidney., Methods: Mouse kidneys were challenged by transient brief episodes of sublethal ischemia followed by subsequent prolonged ischemia. DC abundance and maturation in the spleen and kidney were measured by flow cytometry and immunohistochemical staining. To confirm the function of mature DCs in the renoprotective effect of IPC on renal ischemia-reperfusion injury the A2 adenosine receptor (A2AR) antagonist SCH58261 was administered to stimulate DC maturation prior to assessment of renal functional and histological injury and the inflammatory reaction., Results: Compared with sham-operated animals, preconditioned mice had a reduced injury with less CD11c+ cells, lower levels of the pro-inflammatory cytokine IL-17 and reduced expression of the mature DC marker CCR7. Preconditioned mice also produced more of the anti-inflammatory cytokine IL-10. Both renal cells and splenocytes from these mice had more DCs (CD45+/CD11c+/F4/80-), but fewer of these DCs were mature (CD45+/CD11c+/ F4/80-/MHC-II+/CD80+) compared with those from sham-treated animals, suggesting that the immunomodulatory effect of renal ischemic preconditioning is both local and systemic. Additionally, injection of the A2AR antagonist SCH58261 reversed IPC-induced inhibition of DC maturation and mitigated the protective effect of preconditioning, suggesting that DC maturation contributes to immune cell-mediated ischemic preconditioning., Conclusion: Our results show that DIPC of the kidney provides local and systemic immunosuppression by inhibiting DC maturation and hence mediates a renal protective effect., (© 2018 The Author(s). Published by S. Karger AG, Basel.)

Purpose: Topical hypothermia and local ischemic preconditioning have been shown to reduce renal ischemia-reperfusion (I/R) injury individually. We examined whether combination of both strategies lessens renal I/R injury., Methods: Post right nephrectomy, 40 male Wistar rats were randomly assigned to five experimental protocols performed in the left kidney: topical hypothermia without ischemia (TH), warm ischemia (IR), ischemic preconditioning followed by warm ischemia (IPC+IR), cold ischemia (TH+IR), and ischemic preconditioning followed by cold ischemia (IPC+TH+IR). Eight randomly assigned right kidneys constituted the control group. After 240 min of reperfusion, the left kidney was retrieved to evaluate histological changes, lipid peroxidation and antioxidant enzymes activity. Serum was collected to evaluate urea and creatinine., Results: IPC+TH+IR group revealed no difference to any other group subjected to ischemia in relation to histological changes, lipid peroxidation and antioxidant enzymes activity. Creatinine was lower in IPC+TH+IR group compared with IPC+IR, but showed no difference compared to TH+IR group., Conclusions: Combination of local ischemic preconditioning (IPC) and topical hypothermia conferred no protection in renal I/R injury. Moreover, local IPC solely followed by warm ischemia impaired renal function more than warm ischemia alone.

Contrast-induced acute kidney injury (CI-AKI) is a common complication of many diagnostic and therapeutic cardiovascular procedures. It is associated with longer in-hospital stay, more complicated hospitalization course, and higher in-hospital morbidity and mortality. With increasing use of contrast media in various diagnostic and interventional procedures, the prevalence of CI-AKI is expected to rise. Although pre-hydration with intravenous normal saline is recommended in patients with elevated risk of CI-AKI, this approach is often not feasible in many clinical settings. Remote ischemic conditioning (RIC), elicited by application of one or more, brief, non-injurious episodes of ischemia and reperfusion of a limb, is a promising therapy for preventing or attenuating the deleterious effects of contrast media on the kidney. Although the mechanisms of protection by RIC have not been completely defined, complex humoral, neural, and inflammatory pathways have been hypothesized to be in play. Given that RIC is non-invasive and cheap, it is attractive from clinical and economic perspective as a therapy to protect the kidney from CI-AKI. In this succinct review, we highlight the unifying mechanisms of CI-AKI and provide an overview of proposed biological mechanisms of renal protection by RIC. Emerging pre-clinical and clinical evidence in interventional cardiology is also discussed., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Remote ischemic preconditioning (RIPC) is a strategy to induce resistance in a target organ against the oxidative stress and injury caused by ischemia and reperfusion (IR). RIPC harnesses the body's endogenous protective capabilities through brief episodes of IR applied in organs remote from the target. Few studies have analyzed this phenomenon in the kidney. Furthermore, the window of protection representing RIPC efficacy has not been fully elucidated. Here, we performed a multiomics study to specify those associated with protective effects of RIPC against the IR injury. A total of 30 mice were divided to four groups: sham, IR only, late RIPC + IR, and early RIPC + IR. We found that IR clearly led to tubular injury, whereas both preconditioning groups exhibited attenuated injury after the insult. In addition, renal IR injury produced changes of the metabolome in kidney, serum, and urine specimens. Furthermore, distinctive mRNA and associated protein expression changes supported potential mechanisms. Our findings revealed that RIPC effectively reduces renal damage after IR and that the potential mechanisms differed between the two time windows of protection. These results may potentially be extended to humans to allow non- or minimally invasive diagnosis of renal IR injury and RIPC efficacy.

Purpose:: To evaluate if combination of perconditioning and postconditioning provides improved renal protection compared to perconditioning alone in a model of renal reperfusion injury., Methods:: Thirty rats were assigned into 6 groups: normality; sham; ischemia and reperfusion; postconditioning; perconditioning; perconditioning + postconditioning. Animals were subjected to right nephrectomy and left renal ischemia for 30 minutes. Postconditioning consisted of 3 cycles of 5 min renal perfusion followed by 5 min of renal ischemia after major ischemic period. Perconditioning consisted of 3 cycles of 5 min hindlimb ischemia followed by 5 min of hindlimb perfusion contemporaneously to renal major ischemic period. After 24 hours, kidney was harvested and blood collected to measure urea and creatinine., Results:: Perconditioning obtained better values for creatinine and urea level than only postconditioning (p<0.01); performing both techniques contemporaneously had no increased results (p>0.05). Regarding tissue structure, perconditioning was the only technique to protect the glomerulus and tubules (p<0.05), while postconditioning protected only the glomerulus (p<0.05). Combination of both techniques shows no effect on glomerulus or tubules (p>0.05)., Conclusions:: Perconditioning had promising results on ischemia and reperfusion induced kidney injury, enhanced kidney function and protected glomerulus and tubules. There was no additive protection when postconditioning and perconditioning were combined.

Objective: Sepsis, triggered by microbial infection, is a common and life-threatening systemic illness, often leads to impaired function of vital organs. Ischemic preconditioning induced by transient brief episodes of ischemia is a powerful innate mechanism of organ protection. We have reported that a 15-minute renal ischemic preconditioning substantially attenuated subsequent renal ischemia-reperfusion injury. Here, we investigate whether a brief ischemia and reperfusion in kidney can provide protection at local and remote sites against sepsis-induced organ injury, and whether this protection is microRNA-21 dependent., Design: Laboratory study., Setting: University laboratory., Subjects: Mouse renal tubular epithelial cells, C57BL/6 J wildtype (Animal Center of Fudan University, Shanghai, China) and microRNA-21-/- mice (B6.129-Mir21atm1Smoc, Shanghai Biomodel Organism Science & Technology Development Co. Shanghai, China)., Interventions: Mouse renal tubular epithelial cells were treated with hypoxia (2% oxygen). Renal ischemic preconditioning was induced by bilateral renal pedicle clamping for 15 minutes, and sepsis was induced by a single intraperitoneal injection of lipopolysaccharide at a dose of 20 mg/kg or cecal ligation and puncture in mice., Measurements and Main Results: Mice treated with renal ischemic preconditioning were protected from endotoxemia or polymicrobial sepsis-induced multiple organ injury, including kidneys, heart, liver, and lungs. Renal ischemic preconditioning induced activation of hypoxia-inducible factor-1α in kidneys, which up-regulated microRNA-21 at transcriptional level, subsequently, leading to increased expression of microRNA-21 in serum exosomes and remote organs, resulting in decreased apoptosis and reduced proinflammatory cytokines production in these organs. In vivo knockdown of microRNA-21 or genetic deletion of microRNA-21 abrogated the organoprotective effects conferred by renal ischemic preconditioning. Mechanistically, we discovered that knockdown of microRNA-21 increased programmed cell death protein 4 expression and nuclear factor-kappa B activity, decreased expression of anti-apoptotic B-cell lymphoma-2., Conclusion: MicroRNA-21 is required for local and remote ischemic preconditioning in multiple organ protection against sepsis, and up-regulation of miR-21 may be a potential therapy for sepsis.

Over the course of the last 2 decades, the concept of remote ischemic conditioning (RIC) has attracted considerable research interest, because RIC, in most of its embodiments offers an inexpensive way of protecting tissues against ischemic damage inflicted by a number of medical conditions or procedures. Acute kidney injury (AKI) is a common side effect in the context of various medical procedures, and RIC has been suggested as a means of reducing its incidence. Outcomes regarding kidney function have been reported in numerous studies that evaluated the effects of RIC in a variety of settings (eg, cardiac surgery, interventions requiring intravenous administration of contrast media). Although several individual studies have implied a beneficial effect of RIC in preserving kidney function, 3 recently published randomized controlled trials evaluating more than 1000 patients each (Effect of Remote Ischemic Preconditioning in the Cardiac Surgery, Remote Ischaemic Preconditioning for Heart Surgery, and ERICCA) were negative. However, AKI or any other index of renal function was not a stand-alone primary end point in any of these trials. On the other hand, a range of meta-analyses (each including thousands of participants) have reported mixed results, with the most recent among them showing benefit from RIC, pinpointing at the same time a number of shortcomings in published studies, adversely affecting the quality of available data. The present review provides a critical appraisal of the current state of this field of research. It is the opinion of the authors of this review that there is a clear need for a common clinical trial framework for ischemic conditioning studies. If the current babel of definitions, procedures, outcomes, and goals persists, it is most likely that soon ischemic conditioning will be "yesterday's news" with no definitive conclusions having been reached in terms of its real clinical utility.

Purpose:: To evaluate whether low energy shock wave preconditioning could reduce renal ischemic reperfusion injury caused by renal artery occlusion., Methods:: The right kidneys of 64 male Sprague Dawley rats were removed to establish an isolated kidney model. The rats were then divided into four treatment groups: Group 1 was the sham treatment group; Group 2, received only low-energy (12 kv, 1 Hz, 200 times) shock wave preconditioning; Group 3 received the same low-energy shock wave preconditioning as Group 2, and then the left renal artery was occluded for 45 minutes; and Group 4 had the left renal artery occluded for 45 minutes. At 24 hours and one-week time points after reperfusion, serum inducible nitric oxide synthase (iNOS), neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule-1 (KIM-1), creatinine (Cr), and cystatin C (Cys C) levels were measured, malondialdehyde (MDA) in kidney tissue was detected, and changes in nephric morphology were evaluated by light and electron microscopy., Results:: Twenty-four hours after reperfusion, serum iNOS, NGAL, Cr, Cys C, and MDA levels in Group 3 were significantly lower than those in Group 4; light and electron microscopy showed that the renal tissue injury in Group 3 was significantly lighter than that in Group 4. One week after reperfusion, serum NGAL, KIM-1, and Cys C levels in Group 3 were significantly lower than those in Group 4., Conclusion:: Low-energy shock wave preconditioning can reduce renal ischemic reperfusion injury caused by renal artery occlusion in an isolated kidney rat model.

Remote ischemic preconditioning (rIPC) is a reliable strategy for prevention of injury to various organs. However the mechanism by which it does so is still unclear. In the present study, serum and EVs isolated from ischemic preconditioned right renal venous perfusates were injected into rats with ischemia-reperfusion-injured kidneys immediately after reperfusion. The animals were killed 24h later. Tubular scores and renal function were tested to evaluate the therapeutic effects. To further explore the underlying mechanism, HK-2 cells derived EVs under hypoxia were also administrated to rats with left kidney IRI. Results showed that transient ischemia of the right kidney induced renal tubular epithelial cells to release functional extracellular vesicles (EVs), which were found to alleviate left kidney ischemic reperfusion injury (IRI) by circulation and the EV-depleted serum lost this property. Further, human kidney cells (HK2) were cultured under hypoxic conditions to generate EVs in vitro. These EVs also showed obvious therapeutic effects for renal IRI. Our results suggested that remote ischemic preconditioning plays a therapeutic role in renal IRI through EVs induced by hypoxia., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)

Background: In a multicenter, randomized trial, the authors enrolled patients at high-risk for acute kidney injury as identified by a Cleveland Clinic Foundation score of 6 or more. The authors enrolled 240 patients at four hospitals and randomized them to remote ischemic preconditioning or control. The authors found that remote ischemic preconditioning reduced acute kidney injury in high-risk patients undergoing cardiac surgery. The authors now report on the effects of remote ischemic preconditioning on 90-day outcomes., Methods: In this follow-up study of the RenalRIP trial, the authors examined the effect of remote ischemic preconditioning on the composite endpoint major adverse kidney events consisting of mortality, need for renal replacement therapy, and persistent renal dysfunction at 90 days. Secondary outcomes were persistent renal dysfunction and dialysis dependence in patients with acute kidney injury., Results: Remote ischemic preconditioning significantly reduced the occurrence of major adverse kidney events at 90 days (17 of 120 [14.2%]) versus control (30 of 120 [25.0%]; absolute risk reduction, 10.8%; 95% CI, 0.9 to 20.8%; P = 0.034). In those patients who developed acute kidney injury after cardiac surgery, 2 of 38 subjects in the remote ischemic preconditioning group (5.3%) and 13 of 56 subjects in the control group (23.2%) failed to recover renal function at 90 days (absolute risk reduction, 17.9%; 95% CI, 4.8 to 31.1%; P = 0.020). Acute kidney injury biomarkers were also increased in patients reaching the major adverse kidney event endpoint compared to patients who did not., Conclusions: Remote ischemic preconditioning significantly reduced the 3-month incidence of a composite endpoint major adverse kidney events consisting of mortality, need for renal replacement therapy, and persistent renal dysfunction in high-risk patients undergoing cardiac surgery. Furthermore, remote ischemic preconditioning enhanced renal recovery in patients with acute kidney injury.

Background: Ischaemia reperfusion injury can lead to kidney dysfunction or failure. Ischaemic preconditioning is a short period of deprivation of blood supply to particular organs or tissue, followed by a period of reperfusion. It has the potential to protect kidneys from ischaemia reperfusion injury., Objectives: This review aimed to look at the benefits and harms of local and remote ischaemic preconditioning to reduce ischaemia and reperfusion injury among people with renal ischaemia reperfusion injury., Search Methods: We searched Cochrane Kidney and Transplant's Specialised Register to 5 August 2016 through contact with the Information Specialist using search terms relevant to this review., Selection Criteria: We included all randomised controlled trials measuring kidney function and the role of ischaemic preconditioning in patients undergoing a surgical intervention that induces kidney injury. Kidney transplantation studies were excluded., Data Collection and Analysis: Studies were assessed for eligibility and quality; data were extracted by two independent authors. We collected basic study characteristics: type of surgery, remote ischaemic preconditioning protocol, type of anaesthesia. We collected primary outcome measurements: serum creatinine and adverse effects to remote ischaemic preconditioning and secondary outcome measurements: acute kidney injury, need for dialysis, neutrophil gelatinase-associated lipocalin, hospital stay and mortality. Summary estimates of effect were obtained using a random-effects model, and results were expressed as risk ratios (RR) and their 95% confidence intervals (CI) for dichotomous outcomes, and mean difference (MD) and 95% CI for continuous outcomes., Main Results: We included 28 studies which randomised a total of 6851 patients. Risk of bias assessment indicated unclear to low risk of bias for most studies. For consistency regarding the direction of effects, continuous outcomes with negative values, and dichotomous outcomes with values less than one favour remote ischaemic preconditioning. Based on high quality evidence, remote ischaemic preconditioning made little or no difference to the reduction of serum creatinine levels at postoperative days one (14 studies, 1022 participants: MD -0.02 mg/dL, 95% CI -0.05 to 0.02; I 2 = 21%), two (9 studies, 770 participants: MD -0.04 mg/dL, 95% CI -0.09 to 0.02; I 2 = 31%), and three (6 studies, 417 participants: MD -0.05 mg/dL, 95% CI -0.19 to 0.10; I 2 = 68%) compared to control.Serious adverse events occurred in four patients receiving remote ischaemic preconditioning by iliac clamping. It is uncertain whether remote ischaemic preconditioning by cuff inflation leads to increased adverse effects compared to control because the certainty of the evidence is low (15 studies, 3993 participants: RR 3.47, 95% CI 0.55 to 21.76; I 2 = 0%); only two of 15 studies reported any adverse effects (6/1999 in the remote ischaemic preconditioning group and 1/1994 in the control group), the remaining 13 studies stated no adverse effects were observed in either group.Compared to control, remote ischaemic preconditioning made little or no difference to the need for dialysis (13 studies, 2417 participants: RR 0.85, 95% CI 0.37 to 1.94; I 2 = 60%; moderate quality evidence), length of hospital stay (8 studies, 920 participants: MD 0.17 days, 95% CI -0.46 to 0.80; I 2 = 49%, high quality evidence), or all-cause mortality (24 studies, 4931 participants: RR 0.86, 95% CI 0.54 to 1.37; I 2 = 0%, high quality evidence).Remote ischaemic preconditioning may have slightly improved the incidence of acute kidney injury using either the AKIN (8 studies, 2364 participants: RR 0.76, 95% CI 0.57 to 1.00; I 2 = 61%, high quality evidence) or RIFLE criteria (3 studies, 1586 participants: RR 0.91, 95% CI 0.75 to 1.12; I 2 = 0%, moderate quality evidence)., Authors' Conclusions: Remote ischaemic preconditioning by cuff inflation appears to be a safe method, and probably leads to little or no difference in serum creatinine, adverse effects, need for dialysis, length of hospital stay, death and in the incidence of acute kidney injury. Overall we had moderate-high certainty evidence however the available data does not confirm the efficacy of remote ischaemic preconditioning in reducing renal ischaemia reperfusion injury in patients undergoing major cardiac and vascular surgery in which renal ischaemia reperfusion injury may occur.

Purpose:: To evaluate the effects of tramadol hydrochloride associated to remote ischemic perconditioning on oxidative stress., Methods:: Twenty five male rats (Wistar) underwent right nephrectomy and were distributed into five groups: Sham group (S); Ischemia/Reperfusion group (I/R) with 30 minutes of renal ischemia; Remote ischemic perconditioning group (Per) with three cycles of 10 minutes of I/R performed during kidney ischemia; Tramadol group (T) treated with tramadol hydrochloride (40mg/kg); remote ischemic perconditioning + Tramadol group (Per+T) with both treatments. Oxidative stress was assessed after 24 hours of reperfusion., Results:: Statistical differences were observed in MDA levels between I/R group with all groups (p<0.01), in addition there was difference between Tramadol with Sham, Per and Per+T groups (p<0.05), both in plasma and renal tissue., Conclusion:: Remote ischemic perconditioning was more effective reducing renal ischemia-reperfusion injury than administration of tramadol or association of both treatments.

Purpose:: To evaluate the effects of hypertonic saline solution associated to remote ischemic perconditioning in renal ischemia/reperfusion injury in rats., Methods:: Twenty five male rats (Wistar) underwent right nephrectomy and were distributed into five groups: Sham group (S); Ischemia/Reperfusion group (I/R) with 30 minutes of renal ischemia; Remote ischemic perconditioning group (Per) with three cycles of 10 minutes of I/R performed during kidney ischemia; Hypertonic saline solution group (HSS) treated with hypertonic saline solution (4ml/kg); remote ischemic perconditioning + Hypertonic saline solution group (Per+HSS) with both treatments. After reperfusion, blood samples were collected for BUN and creatinine serum levels analyzes. TBARS were evaluated in plasma and renal tissue to assess oxidative stress. Kidney histopathological examination were performed., Results:: Per+HSS group showed a lower degree of renal dysfunction in relation to I/R group, whereas the technique of remote ischemic perconditioning isolated or associated with saline solution significantly reduced oxidative stress and histological damage., Conclusion:: Remote ischemic perconditioning associated or not to saline solution promoted reduction of acute renal injury induced by ischemia/reperfusion.

BACKGROUND The objective of this study was to determine whether homing of endothelial progenitor cells (EPCs) induced by ischemic preconditioning (IPC) contributed to the protection of renal acute ischemia-reperfusion injury (IRI) in male rats. MATERIAL AND METHODS Forty male Sprague-Dawley rats were randomly divided into four groups, including sham-operated group, IRI-operated group, IPC-treated group and EPCs-treated group. Subsequently, serum samples were collected at 24 and 72 hours after reperfusion, respectively. In addition, histological examination was utilized to assess changes in renal structure. Moreover, immunohistochemical staining, quantitative real-time PCR and Western blotting analysis detected the expression levels of CD31, CD34, vascular endothelial growth factor (VEGF), angiopoietin-1 (Ang-1) and angiopoietin-2 (Ang-2). RESULTS Rats in the EPCS-treated group had significantly reduced levels of blood urea nitrogen and serum creatinine at 24 hours after operation, compared to rats that in the IRI-operated group. At 72 hours after reperfusion, renal function and morphology showed significant improvements in the EPCs-treated group. In addition, CD31+ and CD34+ cells that mostly accumulated in the renal medulla were significantly increased in IPC-treated group at 72 hours (p<0.05). Compared to the IRI-operated group, the number of EPCs in the kidneys was markedly increased at 72 hours following reperfusion in the IPC-treated group. In addition, expression levels of VEGF, Ang-1 and Ang-2 in the kidneys of the IPC-treated and EPCs-treated rats were significantly increased compared to the IRI-operated group. CONCLUSIONS These results provided evidence that IPC-mediated homing of EPCs played an important role in the protection of renal acute IRI, involving promotion of cell proliferation and angiogenesis through release of several angiogenic factors, such as VEGF, Ang-1, and Ang-2.

Objective: Dysfunctional metabolisms have contributed towards ischemia-reperfusion (I/R) injury. However, the role of remote ischemic preconditioning (RIP) in I/R injury is not well known. The present study showed alleviated I/R injury in kidneys treated with RIP., Materials and Methods: We utilized GC/MS-based metabolomics to characterize the variation of metabolomes., Results: Metabolic category using differential metabolites showed the lower percentage of amino acids in I/R group in comparison to RIP+I/R group, confirming the importance of amino acid metabolism in RIP-treated rat kidney. Further, pathway enrichment analysis showed alanine, aspartate and glutamate metabolism to be involved in the beneficial effects of RIP during renal I/R injury. Furthermore, another crucial enrichment pathway is biosynthesis of unsaturated fatty acids. Other vital metabolites detected in independent component analysis (ICA) analysis were d-glucose, lactic acid and cholesterol. The variation tendency of above-mentioned metabolites was overall consistent with the protective nature of RIP., Conclusions: These findings elicited a viewpoint that metabolic strategy affected by RIP are linked to underlying mechanisms of RIP and highlighted the importance of metabolic strategy against I/R injury.

Background/aims: Diabetes mellitus can exacerbate renal ischemia-reperfusion (I/R) injury (RI/RI). The aim of the present study was to evaluate the protective effect of GSK-3β inhibition (TDZD-8) on I/R-induced renal injury through the Nrf2/HO-1 pathway in a streptozocin (STZ)-induced diabetic rat model., Methods: STZ-induced diabetic rats preconditioned with TDZD-8 and ZnPP were subjected to renal I/R. The extent of renal morphologic lesions. Renal function was assessed from blood urea nitrogen (BUN) and serum creatinine (Scr), as determined utlizing commercial kits. Oxidative stress and inflammatory activity in the kidney tissue was estimated from levels of malondialdehyde (MDA), interleukin-10 (IL-10), tumor necrosis factor-α (TNF-α), and nitric oxide (NO), as well as the activities of superoxide dismutase (SOD) and glutathione (GSH) using qRT-PCR and ELISA. The expressions of Nrf2, HO-1, Bcl-2 and NF-κB in the renal tissue were measured by qRT-PCR and western blotting., Results: I/R-induced renal inflammation was reduced significantly by TDZD-8 pretreatment. Preconditioning with TDZD-8 suppressed NF-κB expression and enhanced Bcl-2 expression in the renal tissue. The upregulated level of malondialdehyde (MDA), and reduced activities of superoxide dismutase (SOD) and glutathione (GSH) in I/R-shocked rats were markedly restored by TDZD-8 pretreatment. Furthermore, pretreatment with TDZD-8 enhanced activation of the Nrf2/HO-1 pathway in the renal tissue of diabetic RI/RI rats., Conclusion: These findings suggest that preconditioning with TDZD-8 may protect the kidney from I/R-induced damage via the activation of the Nrf2/HO-1 pathway in STZ-induced diabetic rats. Further detailed studies are needed to further clarify the underlying mechanisms., (© 2017 The Author(s). Published by S. Karger AG, Basel.)

Background/aims: Chelerythrine (CHE), a benzophenanthridine alkaloid, is a potent, selective, and cell-permeable protein kinase C (PKC) inhibitor. The purpose of the present study was to evaluate the effect of CHE on myocardial recovery after renal ischemia/reperfusion (I/R)-induced myocardial injury (RI/RMI) in a streptozocin (STZ)-induced diabetic rat model., Methods: Diabetes mellitus (DM) rats preconditioned with CHE and D, L-propargylglycine (PAG) were subjected to renal I/R. The extent of cardiac morphologic lesions and the biochemical markers of cardiorenal function and oxidative stress were detected utilizing hematoxylin-eosin staining, commercial kits, and enzyme-linked immunoassay, respectively. The expressions of cystathionine-γ-lyase (CSE), PKC-α, PKC-β2, and nuclear factor-kappa B (NF-κB) in the rat myocardial tissue were measured utilizing western blotting., Results: Renal I/R treatment resulted in myocardial injury. CHE-preconditioning promoted the recovery from myocardial damage by ameliorating the biochemical parameters of myocardial injury, reducing oxidative stress, increasing the H2S level, up-regulating the expression of CSE, and down-regulating the expressions of PKC-α, PKC-β2, and NF-κB., Conclusion: These findings suggest that CHE-pretreatment may exert a protective effect on the myocardium against RI/RMI by activating endogenous CSE/H2S via PKC/NF-κB pathway in STZ-induced diabetic rats. Further studies are needed defining underlying mechanisms., (© 2017 The Author(s). Published by S. Karger AG, Basel.)

Remote ischemic preconditioning (RIPC) is an intriguing approach which exposes a remote organ/tissue to a non-lethal transient ischemia/reperfusion (I/R) in order to potentiate the resistance of the desired organ/tissue against the next unwanted I/R. It has been suggested that RIPC exerts its effect through neuronal and hormonal pathways. The underlying mechanisms of RIPC are obscure and should be elucidated. In this study, we induced RIPC in mice using 3 cycles of 5 min ischemia alternating with 5 min reperfusion of the left renal artery. Renal failure was induced in mice by intra-peritoneal (i.p.) injection of 200 mg/kg body weight of gentamicin twice per day for 4 consecutive days. Global hippocampal ischemia reperfusion (I/R) was performed by bilateral carotid artery occlusion for 20 min followed by reperfusion for 72 h. Moreover, the retention trial of passive avoidance test was determined 72 h after global ischemia. Histopathological changes of hippocampus neurons were observed using Nissl staining to detect neuronal loss. Finally, terminal deoxynucleotidyl transferase mediated dUTP nick end-labeling (TUNEL) was performed to assess the status of apoptotic cells in the hippocampus. The results of this study suggest that renal ischemic preconditioning is a good candidate for prevention of I/R-induced hippocampal injury. However, RRPC (remote renal preconditioning) failed to exert a neuroprotective effect in mice with renal failure (RF), indicating the probable role of a humoral factor which is released from kidneys in response to ischemia. In agreement with this hypothesis, treatment of mice with rhEPO (5000 IU/kg intraperitoneal) before induction of RRPC restored the neuroprotective effects of RRPC in RF mice. Accordingly, it is plausible to expect that erythropoietin is released from kidneys to act as a mediator for RRPC-induced neuroprotective effects. Renal ischemic preconditioning prevents I/R-induced hippocampal injury. In contrast, renal failure hampers protective effects of RRPC, while exogenous administration of erythropoietin (EPO) significantly prevents the inhibiting effects of renal failure.

Purpose:: To analyze the influence of chlorpromazine on renal histology of rats submitted to ischemia and reperfusion injury., Methods:: Sixteen Wistar rats - split in two groups - have been used: control group, receiving 3 mg/kg isotonic saline solution through caudal vein, and, the chlorpromazine group, receiving 3 mg/kg-IV of such medication. The nephrectomy of the left kidney lower third was carried out; immediately, the test-drug was administrated. After 15 minutes of test-drug administration, the renal pedicle was clamped; in 60 minutes of ischemia it was released. After 24 hours of the renal reperfusion, the rats were, once more, anesthetized and submitted to total left nephrectomy, and, afterwards, to euthanasia. Histological findings regarding ischemia have been evaluated and compared between the groups., Results:: There was no statistical difference related to inferior renal pole histological analysis. Regarding 60-minute renal ischemia, chlorpromazine has statistically reduced the accrual of leucocytes within the vasa recta renis (p=0.036) and the congestion of peritubular capillaries (p=0.041). When conducting joint analysis of histological patterns, the control group showed a median score of 11 and chlorpromazine group of 5.5 (p=0.036)., Conclusion:: Chlorpromazine significantly reduced the occurrence of secondary damage to ischemia and reperfusion process in the overall histological analysis.

This study had two objectives: 1) to determine whether preconditioning cultured proximal tubular cells (PTCs) with pharmacological activators of AMP-activated protein kinase (AMPK) protects these cells from apoptosis induced by metabolic stress in vitro and 2) to assess the effects of preconditioning mice with these agents on the severity of ischemic acute renal kidney injury (AKI) in vivo. We demonstrate that preconditioning PTCs with 5-aminoimidazole-4-carboxamide-1-β-d-ribofuranoside (AICAR) or A-769662 reduces apoptosis of PTCs induced by subsequent stress. We also show that the reduction in cell death during metabolic stress associated with pretreatment by AMPK activators is associated with an increase in the cytosolic level of ATP, which is mediated by an increase in the rate of glycolysis. In addition, we provide evidence that the effect of AMPK activators on glycolysis is mediated, at least in part, by an increased uptake of glucose, and by the induction of hexokinase II (HK II) expression. Our data also show that the increased in HK II expression associated with preconditioning with AMPK activators is mediated by the activation (phosphorylation) of the cAMP-response element binding protein (CREB). We also provide entirely novel evidence that that A-79662 is substantially more effective than AICAR in mediating these alterations in PTCs in vitro. Finally, we demonstrate that preconditioning mice with AICAR or A-769662 substantially reduces the severity of renal dysfunction and tubular injury in a model of ischemic AKI in vivo and that the efficacy of AICAR and A-768662 in ameliorating ischemic AKI in vivo is comparable.

Objective: In this study, we will review the most recently proposed mechanisms for remote ischemic preconditioning and summarize the past 10 years of clinical studies, as well as potential reasons for why, despite over 20 years of research on remote ischemic preconditioning, it is not routinely used in the pediatric critical care patient. In addition, future directions for remote ischemic preconditioning research will be discussed., Data Sources: We searched the PubMed database for relevant literature., Study Selection and Data Extraction: In PubMed, the search terms "ischemic preconditioning" and "remote preconditioning" were used. Randomized controlled trials published from 2006 until the present time that used a blood pressure cuff to induce remote ischemic preconditioning were included. We also reviewed the reference lists of the articles found in the PubMed search and included those thought to contribute to the objectives. All studies pertaining to remote ischemic preconditioning that included pediatric patients were reviewed., Data Synthesis and Conclusions: Differences in study outcomes in the effect of remote ischemic preconditioning on organ protection have been reported and may have played a large role in limiting the translation of findings into routine clinical practice. Ongoing efforts to protocolize the remote ischemic preconditioning technique in large multicenter trials with clearly delineated patient risk groups, including the use of biomarkers for enrichment, may help to ultimately determine if this procedure can be safely and effectively used for critically ill children.

Renal ischemia/reperfusion (I/R) can lead to impaired urine concentration ability and increased fractional excretion of sodium (FeNa). Local ischemic preconditioning improves renal water and sodium handling after I/R injury. Here, we investigate whether remote ischemic perconditioning (rIPeC) prevents dysregulation of renal water and salt handling in response to I/R injury and mechanisms that may be involved. Rats were subjected to right nephrectomy and randomized into a sham group or an I/R group. In the I/R group, rats were subjected to 37 min of renal ischemia and 3 days of reperfusion. rIPeC was applied to the abdominal aorta. Blood and urine were collected on day 3 postoperatively for clearance studies. The expression of aquaporins (AQPs) and the sodium transporter Na-K-ATPase were analyzed using immunoblotting and immunohistochemistry. I/R injury resulted in polyuria, increased FeNa, and decreased urine osmolality compared to sham rats. rIPeC attenuated the increase in FeNa and the decrease in urine osmolality. Expression of AQP1, AQP2, phosphorylated AQP2 (pAQP2), and Na-K-ATPase was downregulated in I/R rats. rIPeC attenuated the reductions in AQP2 and pAQP2 expression. Immunohistochemistry revealed decreased labeling of Na-K-ATPase in the outer medulla in I/R kidneys compared to kidneys from sham and I/R + rIPeC rats. After renal ischemia, the expression of Na-K-ATPase was substantially reduced in the outer medullary thick ascending limb. In conclusion, our data suggest that rIPeC might prevent dysregulation of renal water and salt handling via regulation of AQP2 expression and phosphorylation as well as via regulation of Na-K-ATPase expression in I/R rat kidneys., (© 2016 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society.)

Background: It has been reported that nafamostat mesilate (NM) inhibits inflammatory injury via inhibition of complement activation in ischemic heart, liver, and intestine. However, it is unclear if NM also inhibits apoptosis in ischemia-reperfusion (IR)-injured kidney. We therefore investigated whether NM attenuates IR renal injury that involves inhibition of apoptosis., Methods: HK-2 cells and male C57BL/6 mice were used for this study. C57Bl/6 mice were divided into 4 groups: sham, NM (2 mg/kg) + sham, IR injury (IR injury; reperfusion 27 minutes after clamping of both the renal artery and vein), and NM + IR injury. Kidneys were harvested 24 hours after IR injury, and functional and molecular parameters were evaluated. For in vitro studies, HK-2 cells were incubated for 6 hours with mineral paraffin oil to induce hypoxic injury, and then treated with various doses of NM to evaluate the antiapoptotic effects., Results: Blood urea nitrogen, serum creatinine levels, and renal tissue injury scores in NM + IR-injured mice were significantly lower than those of control IR mice (all P < .01). NM significantly improved cell survival in hypoxic HK-2 cells (P < .01), significantly decreased renal Bax expression (P < .05), and increased renal Bcl-2 protein levels in IR kidneys and hypoxic HK-2 cells compared with those of the sham and control groups. The numbers of terminal deoxynucleotide transferase-mediated dUTP nick-end labeling- and 8-oxo-2'-deoxyguanosine-positive cells were significantly lower in NM + IR-injured kidneys compared with those in control IR-injured mice (P < .05); NM treatment decreased the expression of inducible and endothelial nitric oxide synthase in IR-injured mice (P < .05)., Conclusions: NM ameliorates IR renal injury via inhibition of apoptosis by, at least in part, lowering nitric oxide overproduction, reducing Bax, and increasing Bcl-2., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Purpose Renal ischemia/reperfusion (I/R) injury is a common clinical problem associated with significant mortality and morbidity. One newly described strategy to reduce this damage is remote perconditioning (RPEC), in which short-time ischemia of a limb during renal ischemia reduces the I/R-induced kidney injury. This study aimed to assess whether RPEC confer protection through changes in pro-inflammatory mediators. Methods Rats were subjected to right nephrectomy and randomized into: sham (no intervention), I/R (subjected to 45-min left renal ischemia) and RPEC group (subjected to four cycles of 5-min I/R of the femoral artery administered during renal ischemia). After 24-h, blood, urine, and kidney samples were collected. Biochemical indicators of renal dysfunction were measured in the cases of Neutrophil gelatinase-associated lipocalin (NGAL), and N-acetyl-B-diglucosaminidase (NAG) activity. Inflammatory cytokines [interleukin (IL)-6 and tumor necrosis factor-alpha, TNF-α] expression in the renal tissues as well as Periodic acid-Schiff stained histological sections were evaluated. Results I/R resulted in renal dysfunction, as evidenced by higher renal NGAL expression and urinary NAG activities. This was accompanied by increased TNF-α and IL-6 expressions as well as histological changes in this group. However, RPEC improved renal histology and function compared with the I/R group. Furthermore, the RPEC group showed decreases in TNF-α and IL-6 expression. Conclusions These results suggest that RPEC reduces the dysfunction and injury associated with I/R of the kidney. This technique reduced the pro-inflammatory cytokine in the kidney. RPEC could be a promising strategy against I/R-induced acute kidney injury partly by down-regulation of inflammatory mediators.

Acute kidney injury (AKI) is a common complication associated with high morbidity and mortality in hospitalized patients. One potential mechanism underlying renal injury is ischaemia/reperfusion injury (IRI), which attributed the organ damage to the inflammatory and oxidative stress responses induced by a period of renal ischaemia and subsequent reperfusion. Therapeutic strategies that aim at minimizing the effect of IRI on the kidneys may prevent AKI and improve clinical outcomes significantly. In this review, we examine the technique of remote ischaemic preconditioning (rIPC), which has been shown by several trials to confer organ protection by applying transient, brief episodes of ischaemia at a distant site before a larger ischaemic insult. We provide an overview of the current clinical evidence regarding the renoprotective effect of rIPC in the key clinical settings of cardiac or vascular surgery, contrast-induced AKI, pre-existing chronic kidney disease (CKD) and renal transplantation, and discuss key areas for future research., (© 2015 Asian Pacific Society of Nephrology.)

Background: Renal ischemia-reperfusion injury (IRI) is a major cause of kidney damage after e.g. renal surgery and transplantation. Ischemic postconditioning (IPoC) is a promising treatment strategy for renal IRI, but early clinical trials have not yet replicated the promising results found in animal studies., Method: We present a systematic review, quality assessment and meta-analysis of the preclinical evidence for renal IPoC, and identify factors which modify its efficacy., Results: We identified 39 publications studying >250 control animals undergoing renal IRI only and >290 animals undergoing renal IRI and IPoC. Healthy, male rats undergoing warm ischemia were used in the vast majority of studies. Four studies applied remote IPoC, all others used local IPoC. Meta-analysis showed that both local and remote IPoC ameliorated renal damage after IRI for the outcome measures serum creatinine, blood urea nitrogen and renal histology. Subgroup analysis indicated that IPoC efficacy increased with the duration of index ischemia. Measures to reduce bias were insufficiently reported., Conclusion: High efficacy of IPoC is observed in animal models, but factors pertaining to the internal and external validity of these studies may hamper the translation of IPoC to the clinical setting. The external validity of future animal studies should be increased by including females, comorbid animals, and transplantation models, in order to better inform clinical trial design. The severity of renal damage should be taken into account in the design and analysis of future clinical trials.

Purpose: To investigate the potential effects of pretreatment with allopurinol on renal ischemia/reperfusion injury (IRI) in a rat model., Methods: Twenty four rats were subjected to right kidney uninephrectomy were randomly distributed into the following three groups (n=8): Group A (sham-operated group); Group B (ischemic group) with 30 min of renal ischemia after surgery; and Group C (allopurinol + ischemia group) pretreated with allopurinol at 50 mg/kg for 14 days. At 72 h after renal reperfusion, the kidney was harvested to assess inflammation and apoptosis., Results: Pretreatment with allopurinol significantly improved renal functional and histological grade scores following I/R injury (p<0.05). Compared with Group B, the expression levels of caspase-3 and Bax were markedly reduced in Group C, meanwhile, whereas expression of bcl-2 was clearly increased (p<0.05). A newly described marker of inflammation, High Mobility Group Box 1(HMGB1), showed reduced expression in Group C (p<0.05)., Conclusion: Pretreatment with allopurinol had a protective effect on kidney ischemia/reperfusion injury, which might be related to the inhibition of HMGB1 expression.

Background: Remote ischemic conditioning (RIC) is the most promising surgical approach to mitigate ischemia and reperfusion (IR) injury. It consists in performing brief cycles of IR in tissues other than those exposed to ischemia. The underlying mechanisms of the induced protection are barely understood, so we evaluated if RIC works enhancing the antioxidant defense of the liver and kidney before IR injury., Materials and Methods: Twenty-one Wistar rats were assigned into three groups as follows: sham, same surgical procedure as in the remaining groups was performed, but no RIC was carried out. RIC 10, RIC was performed, and no abdominal organ ischemia was induced. After 10 min of the end of the RIC protocol, the liver and kidney were harvested. RIC 60, similar procedure as performed in RIC 10, but the liver and the kidney were harvested 60 min. RIC consisted of three cycles of 5-min left hind limb ischemia followed by 5-min left hind limb perfusion, lasting 30 min in total. Samples were used to measure tissue total antioxidant capacity., Results: RIC protocol increased both liver (1.064 ± 0.26 mM/L) and kidney (1.310 ± 0.17 mM/L) antioxidant capacity after 10 min when compared with sham (liver, 0.759 ± 0.10 mM/L and kidney, 1.08 ± 0.15 mM/L). Sixty minutes after the RIC protocol, no enhancement on liver (0.687 ± 0.13 mM/L) or kidney (1.09 ± 0.15 mM/L) antioxidant capacity was detected., Conclusions: RIC works through temporary and short-term enhancement of liver and kidney cells antioxidant defenses to avoid the deleterious consequences of a future IR injury., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Ischemia-reperfusion injury (IRI) is the major cause of acute kidney injury. Remote ischemic conditioning (rIC) performed as brief intermittent sub-lethal ischemia and reperfusion episodes in a distant organ may protect the kidney against IRI. Here we investigated the renal effects of rIC applied either prior to (remote ischemic preconditioning; rIPC) or during (remote ischemic perconditioning; rIPerC) sustained ischemic kidney injury in rats. The effects were evaluated as differences in creatinine clearance (CrCl) rate, tissue tubular damage marker expression, and potential kidney recovery mediators. One week after undergoing right-sided nephrectomy, rats were randomly divided into four groups: sham (n = 7), ischemia and reperfusion (IR; n = 10), IR+rIPC (n = 10), and IR+rIPerC (n = 10). The rIC was performed as four repeated episodes of 5-minute clamping of the infrarenal aorta followed by 5-minute release either before or during 37 minutes of left renal artery clamping representing the IRI. Urine and blood were sampled prior to ischemia as well as 3 and 7 days after reperfusion. The kidney was harvested for mRNA and protein isolation. Seven days after IRI, the CrCl change from baseline values was similar in the IR (δ: 0.74 mL/min/kg [-0.45 to 1.94]), IR+rIPC (δ: 0.21 mL/min/kg [-0.75 to 1.17], p > 0.9999), and IR+rIPerC (δ: 0.41 mL/min/kg [-0.43 to 1.25], p > 0.9999) groups. Kidney function recovery was associated with a significant up-regulation of phosphorylated protein kinase B (pAkt), extracellular regulated kinase 1/2 (pERK1/2), and heat shock proteins (HSPs) pHSP27, HSP32, and HSP70, but rIC was not associated with any significant differences in tubular damage, inflammatory, or fibrosis marker expression. In our study, rIC did not protect the kidney against IRI. However, on days 3-7 after IRI, all groups recovered renal function. This was associated with pAkt and pERK1/2 up-regulation and increased HSP expression at day 7.

Remote ischemic preconditioning (RIPC), which consists of several brief ischemia/reperfusion applied at the remote site of lethal ischemia reperfusion, can, through activating different mechanisms, increase the ability of the body's endogenous protection against prolonged ischemia/reperfusion. Recent studies have shown that RIPC has neuroprotective effects, but its mechanisms are not well elucidated. The present study aimed to determine whether activation of KATP channels in remote renal preconditioning decreases hippocampus damage induced by global cerebral ischemia. RIPC was induced by ischemia of the left renal artery (IPC); 24 h later, global cerebral ischemia reperfusion (IR) was induced by common carotid arteries occlusion. 5hydroxydecanoate (5HD) and glibenclamide (Gli) were injected before of IPC. The levels of malondialdehyde (MDA) and catalase (CAT) activity were assessed in hippocampus. Terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) was assessed to detect apoptotic cells in hippocampus. RIPC inhibited apoptosis by decreasing positive TUNEL cells (P < 0.05). KATP channels blocking with 5HD and Gli markedly increased apoptosis in hippocampal cells in RIPC group (P < 0.001). RIPC decreased MDA level and increased CAT activity in ischemic hippocampus (P < 0.01). Also, 5HD and Gli inhibited the effect of RIPC on MDA level and CAT activity (P < 0.05). The present study shows that RIPC can effectively attenuate programmed cell death, increase activity of CAT, and reduce MDA levels. Blocking of KATP channels inhibited the protective effects of RIPC.