• Cardiorenal syndrome
• Cardiovascular
• Kidney
• Oxidative stress
• TRPM2 channel

• Humans
• TRPM Cation Channels/metabolism
• Cardio-Renal Syndrome/metabolism
• Cardio-Renal Syndrome/physiopathology
• Cardio-Renal Syndrome/drug therapy
• Homeostasis
• Animals
• Calcium/metabolism
• Reactive Oxygen Species/metabolism
• Kidney/metabolism
• Kidney/physiopathology
• Kidney/drug effects
• Cardiovascular System/metabolism
• Cardiovascular System/physiopathology
• Cardiovascular System/drug effects
• Oxidative Stress
• Calcium Signaling/drug effects

• Microvascular damage
• Microvascular endothelial cells
• Microvascular leakage
• Microvascular obstruction

• Humans
• Endothelial Cells/metabolism
• Myocardial Infarction/metabolism
• Myocardium/metabolism
• Myocardial Reperfusion Injury/metabolism
• Heart Failure/metabolism

• U1903212 National Natural Science Foundation of China
• 81870272 National Natural Science Foundation of China
• 2021D04020 Natural Science Foundation of Xinjiang Province
• SKL-HIDCA-2021-XXG1 the State Key Laboratory of Pathogenesis, Prevention and Treatment of Central Asia High Incidence Diseases fund
• SKL-HIDCA-2022-XXG1 the State Key Laboratory of Pathogenesis, Prevention and Treatment of Central Asia High Incidence Diseases fund
• Science and Technology Department of Xinjiang Uygur Autonomous Region

• AMPK/mTOR pathway
• Acute lung injury
• autophagy
• inflammation
• renal ischemic-reperfusion

• ischemia–reperfusion injury
• nerolidol
• renal

• Acute kidney Injury
• Ischemia-reperfusion
• Oxidative stress, and inflammation
• TRP
• TRPM2

• Mice
• Animals
• TRPM Cation Channels/genetics
• TRPM Cation Channels/metabolism
• Reperfusion Injury/metabolism
• Kidney/metabolism
• Transient Receptor Potential Channels/metabolism
• Acute Kidney Injury/metabolism
• Inflammation/metabolism
• Oxidative Stress
• Calcium/metabolism

Delayed graft function (DGF) leads to a reduced graft survival. Donors’ features have been always considered as key pathogenic factors in this setting. The aim of our study was to evaluate the recipients’ characteristics in the development of DGF.

We enrolled 932 kidney graft recipients from 466 donors; 226 recipients experienced DGF. In 290 donors, both recipients presented with early graft function (EGF, group A), in 50 both recipients experienced DGF (group B), and in 126 one recipient presented with DGF and the other with EGF (group C). In group C, we selected 7 couples of DGF/EGF recipients and we evaluated the transcriptomic profile by microarray on circulating mononuclear cells harvested before transplantation. Results were validated by qPCR in an independent group of 25 EGF/DGF couples.

In the whole study group, DGF was associated with clinical characteristics related to both donors and recipient. In group C, DGF was significantly associated with body mass index, hemodialysis, and number of mismatches. In the same group, we identified 411 genes differently expressed before transplantation between recipients discordant for the transplant outcome. Those genes were involved in immune dysfunction and inflammation. In particular, we observed a significant increase in DGF patients in the expression of C–C chemokine receptor type 2 (CCR2), the monocyte chemoattractant protein-1 (MCP-1) receptor. CCR-2 upregulation was confirmed in an independent cohort of patients.

Our results suggest that recipients’ clinical/immunological features, potentially modulated by dialysis, are associated with the development of DGF independently of donors’ features.

• CCR-2
• delayed graft function
• gene expression
• kidney transplantation
• peripheral blood mononuclear cells

• TRPA1
• acute kidney injury
• inflammation
• oxidative stress
• renal tubule cells

• acute kidney injury
• acute rejection
• inflammation
• ischemia reperfusion

Recently, the role of CXCR2 in nociception has been noted. Our studies provide new evidence that the intrathecal administration of its CINC ligands (Cytokine-Induced Neutrophil Chemoattractant; CXCL1-3) induces pain-like behavior in naïve mice, and the effect occurring shortly after administration is associated with the neural location of CXCR2, as confirmed by immunofluorescence. RT-qPCR analysis showed, for the first time, raised levels of spinal CXCR2 after chronic constriction injury (CCI) of the sciatic nerve in rats. Originally, on day 2, we detected escalated levels of the spinal mRNA of all CINCs associated with enhancement of the protein level of CXCL3 lasting until day 7. Intrathecal administration of CXCL3 neutralizing antibody diminished neuropathic pain on day 7 after CCI. Interestingly, CXCL3 is produced in lipopolysaccharide-stimulated microglial, but not astroglial, primary cell cultures. We present the first evidence that chronic intrathecal administrations of the selective CXCR2 antagonist, NVP CXCR2 20, attenuate neuropathic pain symptoms and CXCL3 expression after CCI. Moreover, in naïve mice, this antagonist prevented CXCL3-induced hypersensitivity. However, NVP CXCR2 20 did not diminish glial activation, thus not enhancing morphine/buprenorphine analgesia. These results provide novel insight into the crucial role of CXCR2 in neuropathy based on CXCL3 modulation, which may become a potential therapeutic target in pain treatment.

• CXCL1
• CXCL2
• astroglia
• glia
• microglia

Background: To investigate the expression of long non-coding RNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) in renal ischemia-reperfusion injury and explore its role in acute kidney injury.

Methods: 18 mice were randomly divided into a sham operation group (Sham) and an ischemia-reperfusion group (IR) in which animals were sacrificed at 6 h or 12 h after surgery. The kidneys were harvested to measure the expression of MALAT1 mRNA. HK2 cells were treated with cobalt chloride (CoCl₂) to mimic hypoxia or transfected with siRNA to knockdown MALAT1 before CoCl₂ treatment. After that, MALAT1 was analyzed by RT-PCR (reverse transcription-polymerase chain reaction). HIF-1ɑ (hypoxia-inducible factor-1 alpha) and NF-κB (nuclear factor-kappa B) was measured by Western blot. The concentrations of IL-6 (interleukin-6) and TNF-ɑ (tumor necrosis factor-alpha) in the media were detected by ELISA (enzyme-linked immunosorbent assay).

Results: The expression of MALAT1 in the IR (6 h/12 h) group was significantly higher than that in the sham group. In HK2 cells, MALAT1 was significantly increased at 1 h, 3 h, and 6 h after CoCl₂ treatment but had reduced to the basal level at 12 h and 24 h. Knockdown of MALAT1 by siRNA significantly up-regulated the expression of HIF-1ɑ and NF-κB proteins in CoCl₂-treated HK2 cells. In addition, the concentrations of IL-6 and TNF-ɑ were increased by MALAT1 siRNA transfection in CoCl₂-treated HK2 cells.

Conclusion: The expression of MALAT1 is increased in renal ischemia-reperfusion injury. It is likely that MALAT1 inhibits the hypoxia-induced inflammatory response through the NF-κB pathway.

• Acute kidney injury
• MALAT1
• inflammation
• ischemia/reperfusion
• long non-coding RNA

• Animals
• Antioxidants/metabolism
• Apoptosis/drug effects
• Disease Models, Animal
• Heme Oxygenase (Decyclizing)/metabolism
• Heme Oxygenase-1/metabolism
• Heme Oxygenase-1/pharmacology
• Ischemic Preconditioning/methods
• Kidney/blood supply
• Kidney/metabolism
• Male
• Malondialdehyde/metabolism
• NF-kappa B/metabolism
• Random Allocation
• Rats
• Rats, Sprague-Dawley
• Recombinant Fusion Proteins/metabolism
• Recombinant Fusion Proteins/pharmacology
• Reperfusion Injury/metabolism

Ischaemia/reperfusion (I/R) injury is an underlying complex interrelated patho-physiological process which effects the outcome of many clinical situations, in particular transplantation. Tumor necrosis factor (TNF)-α is a pleiotropic inflammatory cytokine; a trimeric protein encoded within the major histocompatibility complex which plays a pivotal role in this disease process. This review is based at looking into an update, particularly the new insights in the mechanisms of action of TNF antagonist such as infliximab. Infliximab may thus play a dual role in the field of transplantation where it might not only down regulate the I/R injury, it may also have a beneficial role in the reduction of acute rejection.

• Infliximab
• Ischaemia/reperfusion injury
• Tumor necrosis factor-α

Fas ligand (FasL) and tumor necrosis factor (TNF)-α are major pro-apoptotic molecules and also induce inflammation through cytokine and chemokine production. Although precise intracellular mechanisms of action have been reported for each molecule, the differential impact of these molecules on kidney injury in vivo still requires clarification.

We explored the differential impact of FasL and TNF-α upon apoptosis and inflammation in ischemic acute kidney injury using neutralizing anti-FasL antibodies and TNF-α receptor 1 (TNFR1)-deficient mice.

TNFR1 deficiency was associated with a lesser anti-inflammatory effect upon leukocyte infiltration and tubular necrosis than treatment with anti-FasL antibody. Furthermore, the number of TUNEL-positive cells was significantly reduced in anti-FasL antibody-treated mice, whereas it was only partially diminished in TNFR1-deficient mice. In vitro studies confirmed these findings. FasL administration induced both apoptosis and cytokine/chemokine production from cultured tubular epithelial cells. However, TNF-α had a limited effect upon tubular epithelial cells.

In ischemic acute kidney injury, FasL has a greater impact than TNF-α on the apoptosis and inflammatory reaction through cytokine/chemokine production from tubular epithelial cells.

• Chemokine
• Cytokine
• Leukocyte
• Tubular injury

Background. Acute kidney injury (AKI) represents a major clinical problem with high mortality and limited causal treatments. The use of cell therapy has been suggested as a potential modality to improve the course and outcome of AKI.

Methods. We investigated the possible renoprotection of freshly isolated, uncultured adipose tissue-derived stem and regenerative cells (ADRCs) before and after cryopreservation in a rat ischemia–reperfusion (I–R) model of AKI.

Results. We demonstrated that ADRC therapy drastically reduced mortality (survival 100% vs. 57%, ADRC vs. controls, respectively) and significantly reduced serum creatinine (sCr on Day 3: 3.03 ± 1.58 vs. 7.37 ± 2.32 mg/dL, ADRC vs. controls, respectively). Histological analysis further validated a significantly reduced intratubular cast formation, ameliorated acute tubular epithelial cell necrosis and mitigated macrophage infiltration. Furthermore, a reduced RNA expression of CXCL2 and IL-6 was found in the ADRC group which could explain the reduced macrophage recruitment. Use of cryopreserved ADRCs resulted in an equally high survival (90% vs. 33% in the control group) and similarly improved renal function (sCr on Day 3: 4.64 ± 2.43 vs. 7.24 ± 1.40 mg/dL in controls).

Conclusions. Collectively, these results suggest a potential clinical role for ADRC therapy in patients with AKI. Importantly, cryopreservation of ADRCs could offer an autologous treatment strategy for patients who are at high risk for AKI during planned interventions.

Inflammatory reactions in the graft have a pivotal influence on acute as well as long-term graft function. The main reasons for an inflammatory reaction of the graft tissue are rejection episodes, infections as well as ischemia/reperfusion (I/R) injury. The latter is of particular interest as it affects every solid organ during the process of transplantation. I/R injury impairs acute as well as long-term graft function and is associated with an increased number of acute rejection episodes that again affect long-term graft outcome.

I/R injury is the result of ATP depletion during prolonged hypoxia. Further tissue damage results from the reperfusion of the tissue after the ischemic insult. Adaptive cellular responses activate the innate immune system with its Toll-like receptors and the complement system as well as the adaptive immune system. This results in a profound inflammatory tissue reaction with immune cells infiltrating the tissue. The damage is mediated by various cytokines, chemokines, adhesion molecules, and compounds of the extracellular matrix. The expression of these factors is regulated by specific transcription factors with NF-κB being one of the key modulators of inflammation.

Strategies to prevent or treat I/R injury include blockade of cytokines/chemokines, adhesion molecules, NF-κB, specific MAP kinases, metalloproteinases, induction of protective genes, and modulation of the innate immune system. Furthermore, preconditioning of the donor is an area of intense research. Here pharmacological treatment as well as new additives to conventional cold storage solutions have been analyzed together with new techniques for the perfusion of grafts, or methods of normothermic storage that would avoid the problem of cold damage and graft ischemia.

However, the number of clinical trials in the field of I/R injury is limited as compared to the large body of experimental knowledge that accumulated during recent years in the field of I/R injury. Future activities in the treatment of I/R injury should focus on the translation of experimental protocols into clinical trials in order to reduce I/R injury and, thus, improve short- as well as long-term graft outcome.

• Active Transport, Cell Nucleus/drug effects
• Active Transport, Cell Nucleus/physiology
• Adiponectin/metabolism
• Adiponectin/pharmacology
• Animals
• Anti-Inflammatory Agents/metabolism
• Anti-Inflammatory Agents/pharmacology
• Brain Ischemia/drug therapy
• Brain Ischemia/metabolism
• Brain Ischemia/physiopathology
• Cytokines/drug effects
• Cytokines/metabolism
• Cytoprotection/drug effects
• Cytoprotection/physiology
• Disease Models, Animal
• Encephalitis/drug therapy
• Encephalitis/metabolism
• Encephalitis/physiopathology
• Immunoglobulin G/drug effects
• Immunoglobulin G/metabolism
• Infarction, Middle Cerebral Artery/drug therapy
• Infarction, Middle Cerebral Artery/metabolism
• Infarction, Middle Cerebral Artery/physiopathology
• Injections, Intravenous
• Male
• Matrix Metalloproteinase 9/drug effects
• Matrix Metalloproteinase 9/metabolism
• Neuroprotective Agents/metabolism
• Neuroprotective Agents/pharmacology
• Peroxidase/drug effects
• Peroxidase/metabolism
• Rats
• Rats, Sprague-Dawley
• Reperfusion Injury/drug therapy
• Reperfusion Injury/metabolism
• Reperfusion Injury/physiopathology
• Transcription Factor RelA/drug effects
• Transcription Factor RelA/metabolism

• Anemia/etiology
• Hematologic Diseases/etiology
• Hematologic Neoplasms/etiology
• Humans
• Kidney Transplantation/adverse effects
• Leukopenia/etiology
• Lymphohistiocytosis, Hemophagocytic/etiology
• Pancytopenia/etiology
• Polycythemia/etiology
• Thrombotic Microangiopathies/etiology