Immune Cells in Ischemic Acute Kidney Injury

2019 ◽  
Vol 20 (8) ◽  
pp. 770-776 ◽  
Author(s):  
Long Zheng ◽  
Wenjun Gao ◽  
Chao Hu ◽  
Cheng Yang ◽  
Ruiming Rong
Keyword(s):  
Acute Kidney Injury ◽  
Immune Cells ◽  
Immune Cell ◽  
Inflammatory Responses ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Systemic Disease ◽  
Kidney Injury ◽  
Repair Process ◽  
Injured Kidney

Acute kidney injury (AKI) is a systemic disease characterized by acute loss of renal function and accumulation of end products of nitrogen metabolism. Ischemic AKI is the most common cause of AKI, and inflammatory responses are inevitablely involved in ischemic AKI. In the process of ischemic AKI, multiple factors are involved in activating and recruitment of immune cell to the injured kidney. These factors include DAMPs and HIFs released from the injured kidney, increased expression of adhesion molecules, the production of chemokines and cytokines, activation of complement system and TLRs as well as the permeability dysfunction of the renal vascular endothelium. Immune cells of both the innate and adaptive immune systems, such as neutrophils, dendritic cells, macrophages and lymphocytes contribute to the pathogenesis of renal injury after ischemia reperfusion injury (IRI), with some of their subpopulations also participating in the repair process. Numerous studies of immune cells involved in the pathogenesis of AKI have enhanced the understanding of their possible mechanisms in AKI which might become the potential targets for the treatment of ischemic AKI. This review describes the function of the immune cells in the pathogenesis and repair of ischemic AKI and emphasizes the treatment of ischemic AKI potentially targeting them.

scholarly journals PINK1 Kinase Enhances the Repair Effects of Bone Marrow Mesenchymal Stem Cells on Renal Ischemia/Reperfusion-Induced Acute Kidney Injury in Mice

2022 ◽  
Author(s):  
Chenyu Lin ◽  
Wen Chen ◽  
Yong Han ◽  
Yujie Sun ◽  
Xiaoqiong Zhao ◽  
...  
Keyword(s):  
Stem Cells ◽  
Acute Kidney Injury ◽  
Mesenchymal Stem Cells ◽  
Stress Response ◽  
Immune Cells ◽  
Peripheral Blood ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Short Period ◽  
Injured Kidney

Abstract Background: Acute kidney injury (AKI) is a common severe acute syndrome caused by multiple causes, which is characterized by a rapid decline of renal function in a short period. Bone mesenchymal stem cells (BMSCs) are effective in the treatment of AKI. However, it remains unclear about the mechanism of their beneficial effects. PENT-induced kinase 1 (PINK1) may play an important role in the kidney tissue repair. In this study, an endeavor would be made to explore the enhancing effect of PINK1 overexpression on the repair of AKI through BMSCs. Methods: In this study, the ischemia/reperfusion-induced acute kidney injury (IRI-AKI) in mice and the hypoxia-reoxygenation model of cells were established, and the indexes were detected by pathology and immunology experimental.Results: After ischemia/reperfusion, compared with the BMSCs group, the OE PINK1 group had a decreased expression of BUN, the mitigated renal fibrosis , the reduced tissue damage degree. Overexpressed PINK1 could decrease the inflammatory reaction of injured kidney tissues in IRI-AKI mice, the decreased expression of IL-10 in peripheral blood serum; and regulate the distribution of immune cells in the kidney during IRI, the decreased infiltration of lymphocytes, the increased infiltration of macrophages; and reduce the stress response of BMSCs under hypoxia and inflammation; and enhance the stress response of BMSCs to renal tubular epithelial cells(RTECs) under hypoxia and inflammation, the decreased apoptosis rate of RTECs, the decreased release of TNF-α in the cell supernatant, and the decreased proliferation of PBMCs in peripheral blood after hypoxia and reoxygenation; and regulate the autophagy of BMSCs in kidney tissues with IRI-AKI to better repair the injured kidney tissues, the increased expression of LC3-B related to autophagy and the decreased expression of mTOR.Conclusions: In this study, PINK1 overexpression enhances the repair effect of BMSCs on IRI-AKI, and the distribution of injured renal immune cells during IRI regulation by BMSCs. Besides, PINK1 enhances BMSCs and their resistance to the stress response of RTECs under hypoxia and inflammation. In addition, it regulates mitophagy during IRI-AKI. The findings of this study provide a new direction and target for the repair of IRI-AKI through BMSCs.

scholarly journals Role of Endothelial Prolyl-4-Hydroxylase Domain Protein/Hypoxia-Inducible Factor Axis in Acute Kidney Injury

Nephron ◽  
2021 ◽  
pp. 1-6
Author(s):  
Ratnakar Tiwari ◽  
Pinelopi P. Kapitsinou
Keyword(s):  
Acute Kidney Injury ◽  
Inflammatory Responses ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Hypoxia Inducible Factor ◽  
Kidney Injury ◽  
Cell Types ◽  
Endothelial Damage ◽  
Adaptation To Hypoxia ◽  
Low Oxygen

Ischemia reperfusion injury (IRI) results from a cessation or restriction of blood supply to an organ followed by reestablishment of perfusion and reoxygenation. In the kidney, IRI due to transplantation, cardiac surgery with cardiopulmonary bypass, and other major vascular surgeries contributes to acute kidney injury (AKI), a clinical condition associated with significant morbidity and mortality in hospitalized patients. In the postischemic kidney, endothelial damage promotes inflammatory responses and leads to persistent hypoxia of the renal tubular epithelium. Like other cell types, endothelial cells respond to low oxygen tension by multiple hypoxic signaling mechanisms. Key mediators of adaptation to hypoxia are hypoxia-inducible factors (HIF)-1 and -2, transcription factors whose activity is negatively regulated by prolyl-hydroxylase domain proteins 1 to 3 (PHD1 to PHD3). The PHD/HIF axis controls several processes determining injury outcome, including ATP generation, cell survival, proliferation, and angiogenesis. Here, we discuss recent advances in our understanding of the endothelial-derived PHD/HIF signaling and its effects on postischemic AKI.

scholarly journals Role of Mitochondrial Therapy for Ischemic-Reperfusion Injury and Acute Kidney Injury

Nephron ◽  
2021 ◽  
pp. 1-6
Author(s):  
Navjot Pabla ◽  
Amandeep Bajwa
Keyword(s):  
Acute Kidney Injury ◽  
Reperfusion Injury ◽  
Mammalian Cells ◽  
Immune Cell ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Parenchymal Cell ◽  
Kidney Injury ◽  
Atp Depletion ◽  
Preclinical Models

Acute kidney injury (AKI) is a common clinical disorder associated with decline in renal function because of ischemic and nephrotoxic insults. The pathophysiology of AKI involves multiple cellular mechanisms, such as kidney parenchymal cell (epithelial and endothelial) dysfunction and immune-cell infiltration. Mitochondrial injury which causes ATP depletion and triggers apoptosis and necrosis is at the heart of ischemia reperfusion injury (IRI). Pharmacological (SS-31 or MitoQ), cellular (dendritic cells or mesenchymal stem cells), or genetic strategies that either directly or indirectly preserve mitochondrial integrity and function have been shown to mitigate IRI-linked AKI in preclinical models. Interestingly, isolated mitochondria have been recently shown to be taken up by various mammalian cells resulting in incorporation of transplanted mitochondria into the endogenous mitochondrial network of recipient cells and contributing to protection from ischemic injury in various preclinical models of ischemia including the heart, liver, and kidneys. The mini review summarizes the current available therapeutic strategies that improve kidney function by targeting mitochondria health.

scholarly journals Exogenous Wnt1 Prevents Acute Kidney Injury and Its Subsequent Progression to Chronic Kidney Disease

2021 ◽  
Vol 12 ◽  
Author(s):  
Xue Hong ◽  
Yanni Zhou ◽  
Dedong Wang ◽  
Fuping Lyu ◽  
Tianjun Guan ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Acute Kidney Injury ◽  
Kidney Disease ◽  
Inflammatory Responses ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Blood Biochemical

Studies suggest that Wnt/β-catenin agonists are beneficial in the treatment of acute kidney injury (AKI); however, it remains elusive about its role in the prevention of AKI and its progression to chronic kidney disease (CKD). In this study, renal Wnt/β-catenin signaling was either activated by overexpression of exogenous Wnt1 or inhibited by administration with ICG-001, a small molecule inhibitor of β-catenin signaling, before mice were subjected to ischemia/reperfusion injury (IRI) to induce AKI and subsequent CKD. Our results showed that in vivo expression of exogenous Wnt1 before IR protected mice against AKI, and impeded the progression of AKI to CKD in mice, as evidenced by both blood biochemical and kidney histological analyses. In contrast, pre-treatment of ICG-001 before IR had no effect on renal Wnt/β-catenin signaling or the progression of AKI to CKD. Mechanistically, in vivo expression of exogenous Wnt1 before IR suppressed the expression of proapoptotic proteins in AKI mice, and reduced inflammatory responses in both AKI and CKD mice. Additionally, exogenous Wnt1 inhibited apoptosis of tubular cells induced by hypoxia-reoxygenation (H/R) treatment in vitro. To conclude, the present study provides evidences to support the preventive effect of Wnt/β-catenin activation on IR-related AKI and its subsequent progression to CKD.

scholarly journals NLRP3 associated with chronic kidney disease progression after ischemia/reperfusion-induced acute kidney injury

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Zhihuang Zheng ◽  
Kexin Xu ◽  
Chuanlei Li ◽  
Chenyang Qi ◽  
Yili Fang ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Acute Kidney Injury ◽  
Kidney Disease ◽  
Immune Cell ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Chronic Phase ◽  
Kidney Injury ◽  
Receptor Protein ◽  
Tubular Damage

AbstractNod-like receptor protein 3 (NLRP3), as an inflammatory regulator, has been implicated in acute kidney injury (AKI). Failed recovery after AKI can lead to chronic kidney disease (CKD). However, the role of NLRP3 in the AKI-CKD transition is still unknown. A mild or severe AKI mouse model was performed by using ischemia-reperfusion injury (IRI). We evaluated the renal NLRP3 expression in acute and chronic phases of ischemic AKI, respectively. Although serum creatinine (Cr) and blood urea nitrogen (BUN) levels in AKI chronic phase were equivalent to normal baseline, histological analysis and fibrotic markers revealed that severe AKI-induced maladaptive tubular repair with immune cell infiltration and fibrosis. Tubular damage was restored completely in mild AKI rather than in severe AKI. Of note, persistent overexpression of NLRP3 was also found in severe AKI but not in mild AKI. In the severe AKI-induced chronic phase, there was a long-term high level of NLRP3 in serum or urine. Overt NLRP3 was mainly distributed in the abnormal tubules surrounded by inflammatory infiltrates and fibrosis, which indicated the maladaptive repair. Renal Nlrp3 overexpression was correlated with infiltrating macrophages and fibrosis. Renal NLRP3 signaling-associated genes were upregulated after severe AKI by RNA-sequencing. Furthermore, NLRP3 was found increased in renal tubular epitheliums from CKD biopsies. Together, persistent NLRP3 overexpression was associated with chronic pathological changes following AKI, which might be a new biomarker for evaluating the possibility of AKI-CKD transition.

scholarly journals Reducing Inflammatory Cytokine Production from Renal Collecting Duct Cells by Inhibiting GATA2 Ameliorates Acute Kidney Injury

2017 ◽  
Vol 37 (22) ◽  
Author(s):  
Lei Yu ◽  
Takashi Moriguchi ◽  
Hiroshi Kaneko ◽  
Makiko Hayashi ◽  
Atsushi Hasegawa ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Inflammatory Cytokines ◽  
Inflammatory Cytokine ◽  
Cytokine Production ◽  
Ischemia Reperfusion Injury ◽  
Collecting Duct ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Cytokine Gene Expression ◽  
Renal Tubular Cell

ABSTRACT Acute kidney injury (AKI) is a leading cause of chronic kidney disease. Proximal tubules are considered to be the primary origin of pathogenic inflammatory cytokines in AKI. However, it remains unclear whether other cell types, including collecting duct (CD) cells, participate in inflammatory processes. The transcription factor GATA2 is specifically expressed in CD cells and maintains their cellular identity. To explore the pathophysiological function of GATA2 in AKI, we generated renal tubular cell-specific Gata2 deletion (G2CKO) mice and examined their susceptibility to ischemia reperfusion injury (IRI). Notably, G2CKO mice exhibited less severe kidney damage, with reduced granulomacrophagic infiltration upon IRI. Transcriptome analysis revealed that a series of inflammatory cytokine genes were downregulated in GATA2-deficient CD cells, suggesting that GATA2 induces inflammatory cytokine expression in diseased kidney CD cells. Through high-throughput chemical library screening, we identified a potent GATA inhibitor. The chemical reduces cytokine production in CD cells and protects the mouse kidney from IRI. These results revealed a novel pathological mechanism of renal IRI, namely, that CD cells produce inflammatory cytokines and promote IRI progression. In injured kidney CD cells, GATA2 exerts a proinflammatory function by upregulating inflammatory cytokine gene expression. GATA2 can therefore be considered a therapeutic target for AKI.

scholarly journals Urinary N-Acetyl-Beta-D-Glucosaminidase Activity in Rat Experimental Ischemic and Toxic Models of Acute Kidney Injury

2017 ◽  
Vol 74 (1) ◽  
pp. 105
Author(s):  
Razvan Andrei CODEA ◽  
Mircea MIRCEAN ◽  
Sidonia Alina BOGDAN ◽  
Andras Laszlo NAGY ◽  
Alexandra BIRIS ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Experimental Model ◽  
Wistar Rats ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Control Group ◽  
Tubular Injury ◽  
Group 2 ◽  
Group 1

The identification of a suitable prevention method which facilitates limiting the deleterious effects of acute kidney injuries is highly required. In order to identify a proper treatment for acute kidney injuries, a suitable experimental model that replicates the structural, metabolic and inflammatory lesions that occur in the natural acute injured kidney is highly necessary. Intense urinary NAG activity can be found in a variety of renal disease such as toxic nephropathies, ischemic renal injury following cardiac surgery or renal transplantation but also in glomerular disease especially in diabetic nephropathy. Rises in urinary NAG enzyme activity strongly suggests tubular cell damage and support NAG enzyme as a biomarker of renal tubular injury. The aim of this paper is to obtain a stable in vivo acute kidney injury experimental model, in Wistar, rats and to evaluate the urinary activity of N-acetyl-β-D-glucosaminidase (NAG) enzyme, blood levels of urea and creatinine and microstructural renal alterations induced by ischemia/reperfusion injury respectively gentamicin nephrotoxicity. For this purpose we have used a rat experimental model. Adult male Wistar rats weighing 250-300 g were randomly divided into 3 groups with 8 rats in each group. Group 1 served as a model for the renal ischemia/reperfusion injury experiment, group 2 served for toxic kidney injury experimental model and group 3 served as control group. All individuals in both groups 1 and 2 presented marked elevations in blood urea and creatinine at the moment of euthanasia (day 3 for group 1 and day 9 for group 2) compared to the control group where biochemical values remained within normal limits. Urine analysis of both group 1 and 2 showed marked urinary NAG index activity which suggests acute tubular injury, suggestion confirmed by histological evaluation of the renal parenchyma sampled from this subjects

scholarly journals P0511ENHANCER AND SUPER-ENHANCER DYNAMICS IN REPAIR AFTER ISCHEMIC ACUTE KIDNEY INJURY

2020 ◽  
Vol 35 (Supplement_3) ◽  
Author(s):  
Julia Wilflingseder ◽  
Michaela Willi ◽  
Hye Kyung Lee ◽  
Hannes Olauson ◽  
Jakub Jankowsky ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Transcription Factors ◽  
Small Molecule ◽  
Ischemia Reperfusion Injury ◽  
Specific Binding ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Kidney Cortex ◽  
Super Enhancer

Abstract Background and Aims The endogenous repair process of the mammalian kidney allows rapid recovery after acute kidney injury (AKI) through robust proliferation of tubular epithelial cells. There is currently limited understanding of which transcriptional regulators activate these repair programs and how transcriptional dysregulation leads to maladaptive repair. Here we investigate the existence of enhancer dynamics in the regenerating mouse kidney. Method RNA-seq and ChIP-seq (H3K27ac, H3K4m3, BRD4, POL2 and selected transcription factors) were performed on samples from repairing kidney cortex 2 days after ischemia/reperfusion injury (IRI) to identify activated genes, transcription factors, enhancer and super-enhancers associated with kidney repair. Further we investigated the role of super-enhancer activation in kidney repair through pharmacological BET inhibition using the small molecule JQ1 in vitro and in acute kidney injury models in vivo. Results Response to kidney injury leads to genome-wide alteration in enhancer repertoire in-vivo. We identified 16,781 enhancer sites (H3K27ac and BRD4 positive, H3K4me3 negative binding) active in SHAM and IRI samples; 6,512 lost and 9,774 gained after IRI. The lost and gained enhancer sites can be annotated to 62% and 63% of down- and up-regulated transcripts at day 2 after kidney injury, respectively. Super-enhancer analysis revealed 164 lost and 216 gained super-enhancer sites at IRI day 2. 385 super-enhancers maintain activity before and after injury. ChIP-seq profiles of selected transcription factors based on motif analysis show specific binding at corresponding enhancer sites. We observed lost enhancer binding of HNF4A and GR mainly at kidney related enhancer elements. In contrast, STAT3 showed increased binding at injury induces enhancer elements. No dynamic was observed for STAT5. Both transcription factor groups show corresponding mRNA changes after injury. Pharmacological inhibition of enhancer and super-enhancer activity by BRD4 inhibition (JQ1: 50mg/kg/day) before IRI leads to suppression of 40% of injury-induced transcripts associated with cell cycle regulation and significantly increased mortality between days 2 and 3 after AKI. Conclusion This is the first demonstration of enhancer and super-enhancer function in the repairing kidney. In addition, our data call attention to potential caveats for use of small molecule inhibitors of BET proteins that are currently being tested in clinical trials in cancer patients who are at risk for AKI. Our analyses of enhancer dynamics after kidney injury in vivo have the potential to identify new targets for therapeutic intervention.

scholarly journals Antioxidative, Antiapoptotic, and Anti-Inflammatory Effects of Apamin in a Murine Model of Lipopolysaccharide-Induced Acute Kidney Injury

Molecules ◽  
2020 ◽  
Vol 25 (23) ◽  
pp. 5717 ◽  
Author(s):  
Jung-Yeon Kim ◽  
Jaechan Leem ◽  
Kwan-Kyu Park
Keyword(s):  
Oxidative Stress ◽  
Acute Kidney Injury ◽  
Immune Cell ◽  
Inflammatory Responses ◽  
Tissue Injury ◽  
Therapeutic Option ◽  
Nicotinamide Adenine Dinucleotide Phosphate ◽  
Kidney Injury ◽  
Heme Oxygenase 1 ◽  
Anti Inflammatory

Sepsis is the major cause of acute kidney injury (AKI) in severely ill patients, but only limited therapeutic options are available. During sepsis, lipopolysaccharide (LPS), an endotoxin derived from bacteria, activates signaling cascades involved in inflammatory responses and tissue injury. Apamin is a component of bee venom and has been shown to exert antioxidative, antiapoptotic, and anti-inflammatory activities. However, the effect of apamin on LPS-induced AKI has not been elucidated. Here, we show that apamin treatment significantly ameliorated renal dysfunction and histological injury, especially tubular injury, in LPS-injected mice. Apamin also suppressed LPS-induced oxidative stress through modulating the expression of nicotinamide adenine dinucleotide phosphate oxidase 4 and heme oxygenase-1. Moreover, tubular cell apoptosis with caspase-3 activation in LPS-injected mice was significantly attenuated by apamin. Apamin also inhibited cytokine production and immune cell accumulation, suppressed toll-like receptor 4 pathway, and downregulated vascular adhesion molecules. Taken together, these results suggest that apamin ameliorates LPS-induced renal injury through inhibiting oxidative stress, apoptosis of tubular epithelial cells, and inflammation. Apamin might be a potential therapeutic option for septic AKI.

scholarly journals P0558DICLOFENAC ENHANCES RENAL INFLAMMATION IN EXPERIMENTAL SUBCLINICAL ACUTE KIDNEY INJURY (AKI)

2020 ◽  
Vol 35 (Supplement_3) ◽  
Author(s):  
Johanna Störmer ◽  
Faikah Gueler ◽  
Song Rong ◽  
Mi-Sun Jang ◽  
Nelli Shushakova ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Oral Dose ◽  
Single Oral Dose ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Renal Perfusion ◽  
Tubular Atrophy ◽  
Renal Inflammation ◽  
Urine Production

Abstract Background and Aims Diclofenac is frequently used for pain control. In a previous study, we showed that already a single oral dose of diclofenac could reduce renal perfusion in healthy individuals. To investigate the influence of oral diclofenac administration on renal inflammation in the setting of pre-existing renal damage, we used a mouse model of subclinical acute kidney injury (AKI) induced by renal ischemia-reperfusion injury (IRI) followed by diclofenac administration. Method Male CD1 mice (7-8 weeks old) underwent unilateral renal pedicle clamping for 15min to induce subclinical AKI. After reperfusion mice received a single oral dose of 100 or 200mg/kg diclofenac via oral gavage. Vehicle treated mice with unilateral IRI served as control. At day 1, mice were placed into metabolic cages to collect urine. Histology was performed on day 1 and 14 for renal morphology. Inflammation and fibrosis were investigated by immunohistochemistry and qPCR. Results Diclofenac treated mice showed reduced urine production. Morphologically, signs of AKI were more pronounced in diclofenac treated kidneys which also showed more Cox-2 positive tubuli in the cortex. On mRNA expression level the pro-inflammatory markers IL-6 and CXCL2, the chemoattractant for neutrophils, were elevated in the diclofenac group. Early upregulation of the pro-fibrotic markers CTGF and PAI-1 was detected already on d1 after IRI in the diclofenac group and tubular atrophy was pronounced after two weeks. Conclusion Already, a single oral dose of diclofenac causes aggravation of renal inflammation and progressive renal fibrosis in the setting of pre-existing subclinical acute kidney injury.

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