Roles of TRPM7 in Renal Ischemia-Reperfusion Injury

: Ischemia-reperfusion injury (IRI) is a major cause of acute kidney injury (AKI) that is a global health concern associated with high morbidity and mortality. So far, no specific interventions limit injury or improve recovery and survival. Transient receptor potential melastatin 7 (TRPM7), a bifunctional membrane protein, plays key roles in inflammation and cell death. However, the precise role and under-lying mechanism of TRPM7 in IR-induced AKI have not been well defined. Herein, we reviewed the structure and function of TRPM7 as a non-selective ion channel, but Ca2+ and Mg2+-conducting, that mediated the elevation of cytosolic Ca2+ and Mg2+. We then reviewed the mechanism of TRPM7 involved in the pathophysiology of IRI, including inflammatory response, apoptosis and necroptosis, renal microvasculature, as well as maladaptive fibrogenesis leading to chronic kidney disease (CKD). Our previous study has shown that the dynamic change and underlying mechanism of TRPM7 involving in inflammation and apoptosis in in vitro hypoxia/reoxygenation and in vivo renal IRI models. The association between TRPM7, apoptosis and inflammation, as well as related caspase-3, HMGB1 and Bax/Bcl-2 ratio, was also discussed. Disclosing the involvement of TRPM7 in renal IRI might provide new mechanistic insights for a potential biomarker as diagnostic and therapeutic target of AKI.

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VX765, a Specific Caspase-1 Inhibitor, Alleviates Lung Ischemia Reperfusion Injury by Suppressing Endothelial Pyroptosis and Barrier Dysfunction

BioMed Research International ◽

10.1155/2021/4525988 ◽

2021 ◽

Vol 2021 ◽

pp. 1-16

Author(s):

Siyi Wu ◽

Zhao Li ◽

Mengling Ye ◽

Chunxia Liu ◽

Hao Liu ◽

...

Keyword(s):

Protective Effect ◽

Reperfusion Injury ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Glucose Deprivation ◽

High Morbidity ◽

Barrier Dysfunction ◽

Caspase 1

Lung ischemia reperfusion injury (LIRI) is a complex pathophysiological process with high morbidity and mortality. An important pathophysiological characteristic of LIRI is endothelial barrier dysfunction, although the mechanism involved in this process remains unclear. VX765, a specific caspase-1 inhibitor, has been shown to have a protective effect against several diseases including sepsis, atherosclerosis, and glial inflammatory disease. The objective of this study was to determine whether VX765 had a protective effect in LIRI. The results showed that lung ischemia/reperfusion (I/R) and oxygen/glucose deprivation and reoxygenation (OGD/R) induced endothelial pyroptosis and barrier dysfunction characterized by an inflammatory response. Treatment with VX765 successfully alleviated I/R- and OGD/R-induced endothelial pyroptosis and barrier dysfunction by inhibiting caspase-1 in vivo and in vitro. In conclusion, these findings showed that VX765 provided effective protection against lung I/R-induced endothelial pyroptosis and barrier dysfunction.

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Hydroxychloroquine Inhibits Macrophage Activation and Attenuates Renal Fibrosis After Ischemia-Reperfusion Injury

Frontiers in Immunology ◽

10.3389/fimmu.2021.645100 ◽

2021 ◽

Vol 12 ◽

Author(s):

Haofeng Zheng ◽

Yannan Zhang ◽

Jiannan He ◽

Zhe Yang ◽

Rui Zhang ◽

...

Keyword(s):

Reperfusion Injury ◽

Renal Fibrosis ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Tubulointerstitial Fibrosis ◽

Health Concern ◽

Dependent Manner ◽

Renal Tubulointerstitial Fibrosis

Chronic kidney disease (CKD), which is associated with high morbidity, remains a worldwide health concern, while effective therapies remain limited. Hydroxychloroquine (HCQ), which mainly targets toll-like receptor-7 (TLR-7) and TLR-9, is associated with a lower risk of incident CKD. Taking into account that TLR-9 is involved in the development of renal fibrosis and serves as a potential therapy target for CKD, we investigated whether HCQ could attenuate CKD via TLR-9 signal pathway. The effects of HCQ on renal tubulointerstitial fibrosis were further explored using a mouse model of renal tubulointerstitial fibrosis after ischemia/reperfusion injury. Bone marrow-derived macrophages were isolated to explore the effects of HCQ in vitro. Judicious use of HCQ efficiently inhibited the activation of macrophages and MAPK signaling pathways, thereby attenuating renal fibrosis in vivo. In an in vitro model, results showed that HCQ promoted apoptosis of macrophages and inhibited activation of macrophages, especially M2 macrophages, in a dose-dependent manner. Because TLR-7 is not involved in the development of CKD post-injury, a TLR-9 knockout mouse was used to explore the mechanisms of HCQ. The effects of HCQ on renal fibrosis and macrophages decreased after depletion of TLR-9 in vivo and in vitro. Taken together, this study indicated that proper use of HCQ could be a new strategy for anti-fibrotic therapy and that TLR-9 could be a potential therapeutic target for CKD following acute kidney injury.

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N6-methyladenosine demethylase FTO impairs hepatic ischemia–reperfusion injury via inhibiting Drp1-mediated mitochondrial fragmentation

Cell Death and Disease ◽

10.1038/s41419-021-03622-x ◽

2021 ◽

Vol 12 (5) ◽

Author(s):

Ying Dong Du ◽

Wen Yuan Guo ◽

Cong Hui Han ◽

Ying Wang ◽

Xiao Song Chen ◽

...

Keyword(s):

Reperfusion Injury ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Mitochondrial Fragmentation ◽

Hepatic Ischemia ◽

Adeno Associated Virus ◽

Downstream Target ◽

Hepatic Ischemia Reperfusion

AbstractDespite N6-methyladenosine (m6A) is functionally important in various biological processes, its role and the underlying regulatory mechanism in the liver remain largely unexplored. In the present study, we showed that fat mass and obesity-associated protein (FTO, an m6A demethylase) was involved in mitochondrial function during hepatic ischemia–reperfusion injury (HIRI). We found that the expression of m6A demethylase FTO was decreased during HIRI. In contrast, the level of m6A methylated RNA was enhanced. Adeno-associated virus-mediated liver-specific overexpression of FTO (AAV8-TBG-FTO) ameliorated the HIRI, repressed the elevated level of m6A methylated RNA, and alleviated liver oxidative stress and mitochondrial fragmentation in vivo and in vitro. Moreover, dynamin-related protein 1 (Drp1) was a downstream target of FTO in the progression of HIRI. FTO contributed to the hepatic protective effect via demethylating the mRNA of Drp1 and impairing the Drp1-mediated mitochondrial fragmentation. Collectively, our findings demonstrated the functional importance of FTO-dependent hepatic m6A methylation during HIRI and provided valuable insights into the therapeutic mechanisms of FTO.

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The Sodium-Glucose Cotransporter-2 Inhibitor Canagliflozin Alleviates Endothelial Dysfunction Following In Vitro Vascular Ischemia/Reperfusion Injury in Rats

International Journal of Molecular Sciences ◽

10.3390/ijms22157774 ◽

2021 ◽

Vol 22 (15) ◽

pp. 7774

Author(s):

Sevil Korkmaz-Icöz ◽

Cenk Kocer ◽

Alex A. Sayour ◽

Patricia Kraft ◽

Mona I. Benker ◽

...

Keyword(s):

Endothelial Dysfunction ◽

Reperfusion Injury ◽

Vascular Function ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Artery Bypass ◽

Diabetic Rats ◽

Organ Bath ◽

Sodium Glucose Cotransporter

Vascular ischemia/reperfusion injury (IRI) contributes to graft failure and adverse clinical outcomes following coronary artery bypass grafting. Sodium-glucose-cotransporter (SGLT)-2-inhibitors have been shown to protect against myocardial IRI, irrespective of diabetes. We hypothesized that adding canagliflozin (CANA) (an SGLT-2-inhibitor) to saline protects vascular grafts from IRI. Aortic rings from non-diabetic rats were isolated and immediately mounted in organ bath chambers (control, n = 9–10 rats) or underwent cold ischemic preservation in saline, supplemented either with a DMSO vehicle (IR, n = 8–10 rats) or 50µM CANA (IR + CANA, n = 9–11 rats). Vascular function was measured, the expression of 88 genes using PCR-array was analyzed, and feature selection using machine learning was applied. Impaired maximal vasorelaxation to acetylcholine in the IR-group compared to controls was significantly ameliorated by CANA (IR 31.7 ± 3.2% vs. IR + CANA 51.9 ± 2.5%, p < 0.05). IR altered the expression of 17 genes. Ccl2, Ccl3, Ccl4, CxCr4, Fos, Icam1, Il10, Il1a and Il1b have been found to have the highest interaction. Compared to controls, IR significantly upregulated the mRNA expressions of Il1a and Il6, which were reduced by 1.5- and 1.75-fold with CANA, respectively. CANA significantly prevented the upregulation of Cd40, downregulated NoxO1 gene expression, decreased ICAM-1 and nitrotyrosine, and increased PECAM-1 immunoreactivity. CANA alleviates endothelial dysfunction following IRI.

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Overexpression of SP1 restores autophagy to alleviate acute renal injury induced by ischemia-reperfusion through the miR-205/PTEN/Akt pathway

Journal of Inflammation ◽

10.1186/s12950-021-00270-y ◽

2021 ◽

Vol 18 (1) ◽

Author(s):

Chong Huang ◽

Yan Chen ◽

Bin Lai ◽

Yan-Xia Chen ◽

Cheng-Yun Xu ◽

...

Keyword(s):

Reperfusion Injury ◽

Cell Apoptosis ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Renal Ischemia ◽

Akt Pathway ◽

Acute Renal Injury ◽

Injury Model ◽

Renal Ischemia Reperfusion Injury

Abstract Background Acute kidney injury (AKI) is a major kidney disease with poor clinical outcome. SP1, a well-known transcription factor, plays a critical role in AKI and subsequent kidney repair through the regulation of various cell biologic processes. However, the underlying mechanism of SP1 in these pathological processes remain largely unknown. Methods An in vitro HK-2 cells with anoxia-reoxygenation injury model (In vitro simulated ischemic injury disease) and an in vivo rat renal ischemia-reperfusion injury model were used in this study. The expression levels of SP1, miR-205 and PTEN were detected by RT-qPCR, and the protein expression levels of SP1, p62, PTEN, AKT, p-AKT, LC3II, LC3I and Beclin-1 were assayed by western blot. Cell proliferation was assessed by MTT assay, and the cell apoptosis was detected by flow cytometry. The secretions of IL-6 and TNF-α were detected by ELISA. The targeted relationship between miR-205 and PTEN was confirmed by dual luciferase report assay. The expression and positioning of LC-3 were observed by immunofluorescence staining. TUNEL staining was used to detect cell apoptosis and immunohistochemical analysis was used to evaluate the expression of SP1 in renal tissue after ischemia-reperfusion injury in rats. Results The expression of PTEN was upregulated while SP1 and miR-205 were downregulated in renal ischemia-reperfusion injury. Overexpression of SP1 protected renal tubule cell against injury induced by ischemia-reperfusion via miR-205/PTEN/Akt pathway mediated autophagy. Overexpression of SP1 attenuated renal ischemia-reperfusion injury in rats. Conclusions SP1 overexpression restored autophagy to alleviate acute renal injury induced by ischemia-reperfusion through the miR-205/PTEN/Akt pathway.

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In vivo and In vitro PPAR-y Activation Decreases M1-Macrophage Polarization and Improves Liver Ischemia Reperfusion Injury

Transplantation Journal ◽

10.1097/01.tp.0000543674.85457.9b ◽

2018 ◽

Vol 102 ◽

pp. S708

Author(s):

Ivan Linares ◽

Agata Bartczak ◽

Kaveh Farrokhi ◽

Dagmar Kollmann ◽

Moritz Kaths ◽

...

Keyword(s):

Reperfusion Injury ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Macrophage Polarization ◽

Liver Ischemia ◽

M1 Macrophage

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Poly-IC Preconditioning Protects against Cerebral and Renal Ischemia-Reperfusion Injury

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/jcbfm.2011.160 ◽

2011 ◽

Vol 32 (2) ◽

pp. 242-247 ◽

Cited By ~ 29

Author(s):

Amy E B Packard ◽

Jason C Hedges ◽

Frances R Bahjat ◽

Susan L Stevens ◽

Michael J Conlin ◽

...

Keyword(s):

Reperfusion Injury ◽

Inflammatory Responses ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Renal Ischemia ◽

Cortical Cells ◽

Polycytidylic Acid ◽

Populations At Risk

Preconditioning induces ischemic tolerance, which confers robust protection against ischemic damage. We show marked protection with polyinosinic polycytidylic acid (poly-IC) preconditioning in three models of murine ischemia-reperfusion injury. Poly-IC preconditioning induced protection against ischemia modeled in vitro in brain cortical cells and in vivo in models of brain ischemia and renal ischemia. Further, unlike other Toll-like receptor (TLR) ligands, which generally induce significant inflammatory responses, poly-IC elicits only modest systemic inflammation. Results show that poly-IC is a new powerful prophylactic treatment that offers promise as a clinical therapeutic strategy to minimize damage in patient populations at risk of ischemic injury.

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Enhancer of zeste homolog 2 modulates oxidative stress‐mediated pyroptosis in vitro and in a mouse kidney ischemia‐reperfusion injury model

The FASEB Journal ◽

10.1096/fj.201901816r ◽

2019 ◽

Vol 34 (1) ◽

pp. 835-852 ◽

Cited By ~ 5

Author(s):

Hao Liu ◽

Zhiyuan Chen ◽

Xiaodong Weng ◽

Hui Chen ◽

Yang Du ◽

...

Keyword(s):

Oxidative Stress ◽

Reperfusion Injury ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Mouse Kidney ◽

Injury Model ◽

Enhancer Of Zeste ◽

Kidney Ischemia

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Knockout of Trpa1 Exacerbates Renal Ischemia–Reperfusion Injury With Classical Activation of Macrophages

American Journal of Hypertension ◽

10.1093/ajh/hpaa162 ◽

2020 ◽

Author(s):

Shuangtao Ma ◽

Donna H Wang

Keyword(s):

Reperfusion Injury ◽

Transient Receptor Potential ◽

Ischemia Reperfusion Injury ◽

Gene Knockout ◽

Ischemia Reperfusion ◽

Renal Ischemia ◽

Activated Macrophages ◽

Renal Ischemia Reperfusion Injury ◽

Classically Activated Macrophages ◽

Classically Activated

Abstract BACKGROUND Classically activated macrophages contribute to the development of renal ischemia–reperfusion injury (IRI). This study aimed to investigate the role of transient receptor potential ankyrin 1 (Trpa1), a regulator of macrophage activation, in IRI-induced acute kidney injury (AKI) by using the Trpa1 gene knockout (Trpa1−/−) mouse model. METHODS Male 8-week-old Trpa1−/− mice and wild-type (WT) littermates were subjected to renal ischemia for 35 minutes by clamping bilateral renal pedicles under isoflurane anesthesia, and blood and tissue samples were collected 24 hours after reperfusion and analyzed with histological and molecular measurements. RESULTS Following IRI, Trpa1−/− mice developed more deteriorated biochemical and morphological signs of AKI when comparing with WT mice. More classically activated M1 macrophages were found in the kidneys of Trpa1−/− mice comparing with WT mice after IRI, while the counts of alternatively activated M2 macrophages in the kidney were similar between the 2 strains after IRI. Furthermore, significantly higher expression levels of proinflammatory markers including interleukin-1 beta and tumor necrosis factor alpha were detected in the kidney of Trpa1−/− mice compared with WT mice after IRI. The levels of TRPA1 protein in the kidney of WT mice were also decreased after IRI. CONCLUSIONS Our results show that ablation of Trpa1 exacerbates infiltration of classically activated macrophages, renal inflammation, and renal injury in mice after IRI. These findings suggest that activation of TRPA1 may protect against IRI-induced AKI via regulation of macrophage-mediated inflammatory pathway.

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