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 C-type lectin Mincle mediates cell death–triggered inflammation in acute kidney injury

2020 ◽  
Vol 217 (11) ◽  
Author(s):  
Miyako Tanaka ◽  
Marie Saka-Tanaka ◽  
Kozue Ochi ◽  
Kumiko Fujieda ◽  
Yuki Sugiura ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Cell Death ◽  
Free Cholesterol ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Sterile Inflammation ◽  
Renal Tubular Cell ◽  
Renal Tubules ◽  
Underlying Mechanisms

Accumulating evidence indicates that cell death triggers sterile inflammation and that impaired clearance of dead cells causes nonresolving inflammation; however, the underlying mechanisms are still unclear. Here, we show that macrophage-inducible C-type lectin (Mincle) senses renal tubular cell death to induce sustained inflammation after acute kidney injury in mice. Mincle-deficient mice were protected against tissue damage and subsequent atrophy of the kidney after ischemia–reperfusion injury. Using lipophilic extract from the injured kidney, we identified β-glucosylceramide as an endogenous Mincle ligand. Notably, free cholesterol markedly enhanced the agonistic effect of β-glucosylceramide on Mincle. Moreover, β-glucosylceramide and free cholesterol accumulated in dead renal tubules in proximity to Mincle-expressing macrophages, where Mincle was supposed to inhibit clearance of dead cells and increase proinflammatory cytokine production. This study demonstrates that β-glucosylceramide in combination with free cholesterol acts on Mincle as an endogenous ligand to induce cell death–triggered, sustained inflammation after acute kidney injury.

Long non-coding RNA SNHG14 aggravates LPS-induced acute kidney injury through regulating miR-495-3p/HIPK1

2021 ◽  
Author(s):  
Ni Yang ◽  
Hai Wang ◽  
Li Zhang ◽  
Junhua Lv ◽  
Zequn Niu ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Acute Kidney Injury ◽  
Inflammatory Cytokine ◽  
Cytokine Production ◽  
Kidney Injury ◽  
Interaction Network ◽  
High Morbidity ◽  
Abrupt Decrease ◽  
Inflammatory Cytokine Production ◽  
Non Coding Rna

Abstract Acute kidney injury (AKI) is a complex syndrome with an abrupt decrease of kidney function, which is associated with high morbidity and mortality. Sepsis is the common cause of AKI. Mounting evidence has demonstrated that long non-coding RNAs (lncRNAs) play critical roles in the development and progression of sepsis-induced AKI. In this study, we aimed to illustrate the function and mechanism of lncRNA SNHG14 in lipopolysaccharide (LPS)-induced AKI. We found that SNHG14 was highly expressed in the plasma of sepsis patients with AKI. SNHG14 inhibited cell proliferation and autophagy and promoted cell apoptosis and inflammatory cytokine production in LPS-stimulated HK-2 cells. Functionally, SNHG14 acted as a competing endogenous RNA (ceRNA) to negatively regulate miR-495-3p expression in HK-2 cells. Furthermore, we identified that HIPK1 is a direct target of miR-495-3p in HK-2 cells. We also revealed that the SNHG14/miR-495-3p/HIPK1 interaction network regulated HK-2 cell proliferation, apoptosis, autophagy, and inflammatory cytokine production upon LPS stimulation. In addition, we demonstrated that the SNHG14/miR-495-3p/HIPK1 interaction network regulated the production of inflammatory cytokines (TNF-α, IL-6, and IL-1β) via modulating NF-κB/p65 signaling in LPS-challenged HK-2 cells. In conclusion, our findings suggested a novel therapeutic axis of SNHG14/miR-495-3p/HIPK1 to treat sepsis-induced AKI.

scholarly journals P0527AROLE OF PROMOTING INFLAMMATION OF KLF6 IN ACUTE KIDNEY INURY

2020 ◽  
Vol 35 (Supplement_3) ◽  
Author(s):  
Dan Li ◽  
Chenyu Li ◽  
Yan Xu
Keyword(s):  
Inflammatory Cytokines ◽  
Inflammatory Cytokine ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Tnf Α ◽  
Public Dataset ◽  
Anti Inflammatory ◽  
Anti Inflammatory Cytokine ◽  
Pro Inflammatory Cytokines

Abstract Background and Aims Acute kidney injury (AKI), commonly appeared in cardiac arrest, surgery and kidney transplantation which involved in ischemia-reperfusion (IR) injury of kidney. However, the mechanisms underlying inflammatory response in IR AKI is still unclear. Method Public dataset showed kruppel-like factor 6 (KLF6) was significantly highly expressed (P<0.05) in AKI, implies KLF6 might be associated with AKI. To evaluate the mechanism of KLF6 on IR AKI, 30 rats were randomly divided into sham and IR group, and were sacrificed at 0 h, 3 h, 6 h, 12 h or 24 h after IR. Results The results showed KLF6 expression was peaking at 6 h after IR, and the expression of pro-inflammatory cytokines MCP-1 and TNF-α were increased both in serum and kidney tissues after IR, while anti-inflammatory cytokine IL-10 was decreased after IR. Furthermore, in vitro results showed KLF6 knock-down reduced the pro-inflammatory cytokines expression and increased the anti-inflammatory cytokines expression. Conclusion These results suggest that (1) KLF6 might be a novel biomarker for early diagnosis of AKI and (2) targeting KLF6 expression may offer novel strategies to protect kidneys from IR AKI Figure KLF6, AKI, Control Inflammation

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 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.

scholarly journals A mouse model of Townes-Brocks syndrome expressing a truncated mutant Sall1 protein is protected from acute kidney injury

2015 ◽  
Vol 309 (10) ◽  
pp. F852-F863 ◽  
Author(s):  
Sara Hirsch ◽  
Tarek El-Achkar ◽  
Lynn Robbins ◽  
Jeannine Basta ◽  
Monique Heitmeier ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Mouse Model ◽  
Congenital Anomalies ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Acute Injury ◽  
Null Alleles ◽  
Heme Oxygenase 1 ◽  
Adult Kidney

It has been postulated that developmental pathways are reutilized during repair and regeneration after injury, but functional analysis of many genes required for kidney formation has not been performed in the adult organ. Mutations in SALL1 cause Townes-Brocks syndrome (TBS) and nonsyndromic congenital anomalies of the kidney and urinary tract, both of which lead to childhood kidney failure. Sall1 is a transcriptional regulator that is expressed in renal progenitor cells and developing nephrons in the embryo. However, its role in the adult kidney has not been investigated. Using a mouse model of TBS ( Sall1 TBS), we investigated the role of Sall1 in response to acute kidney injury. Our studies revealed that Sall1 is expressed in terminally differentiated renal epithelia, including the S3 segment of the proximal tubule, in the mature kidney. Sall1 TBS mice exhibited significant protection from ischemia-reperfusion injury and aristolochic acid-induced nephrotoxicity. This protection from acute injury is seen despite the presence of slowly progressive chronic kidney disease in Sall1 TBS mice. Mice containing null alleles of Sall1 are not protected from acute kidney injury, indicating that expression of a truncated mutant protein from the Sall1 TBS allele, while causative of congenital anomalies, protects the adult kidney from injury. Our studies further revealed that basal levels of the preconditioning factor heme oxygenase-1 are elevated in Sall1 TBS kidneys, suggesting a mechanism for the relative resistance to injury in this model. Together, these studies establish a functional role for Sall1 in the response of the adult kidney to acute injury.

scholarly journals Cell Death Patterns Due to Warm Ischemia or Reperfusion in Renal Tubular Epithelial Cells Originating from Human, Mouse, or the Native Hibernator Hamster

Biology ◽  
2018 ◽  
Vol 7 (4) ◽  
pp. 48 ◽  
Author(s):  
Theodoros Eleftheriadis ◽  
Georgios Pissas ◽  
Georgia Antoniadi ◽  
Vassilios Liakopoulos ◽  
Ioannis Stefanidis
Keyword(s):  
Lipid Peroxidation ◽  
Acute Kidney Injury ◽  
Cell Death ◽  
Epithelial Cells ◽  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Human Cells ◽  
Tubular Epithelial Cells

Ischemia–reperfusion injury contributes to the pathogenesis of many diseases, with acute kidney injury included. Hibernating mammals survive prolonged bouts of deep torpor with a dramatic drop in blood pressure, heart, and breathing rates, interspersed with short periods of arousal and, consequently, ischemia–reperfusion injury. Clarifying the differences under warm anoxia or reoxygenation between human cells and cells from a native hibernator may reveal interventions for rendering human cells resistant to ischemia–reperfusion injury. Human and hamster renal proximal tubular epithelial cells (RPTECs) were cultured under warm anoxia or reoxygenation. Mouse RPTECs were used as a phylogenetic control for hamster cells. Cell death was assessed by both cell imaging and lactate dehydrogenase (LDH) release assay, apoptosis by cleaved caspase-3, autophagy by microtubule-associated protein 1-light chain 3 B II (LC3B-II) to LC3B-I ratio, necroptosis by phosphorylated mixed-lineage kinase domain-like pseudokinase, reactive oxygen species (ROS) fluorometrically, and lipid peroxidation, the end-point of ferroptosis, by malondialdehyde. Human cells died after short periods of warm anoxia or reoxygenation, whereas hamster cells were extremely resistant. In human cells, apoptosis contributed to cell death under both anoxia and reoxygenation. Although under reoxygenation, ROS increased in both human and hamster RPTECs, lipid peroxidation-induced cell death was detected only in human cells. Autophagy was observed only in human cells under both conditions. Necroptosis was not detected in any of the evaluated cells. Clarifying the ways that are responsible for hamster RPTECs escaping from apoptosis and lipid peroxidation-induced cell death may reveal interventions for preventing ischemia–reperfusion-induced acute kidney injury in humans.

scholarly journals Endothelial STAT3 Modulates Protective Mechanisms in a Mouse Ischemia-Reperfusion Model of Acute Kidney Injury

2017 ◽  
Vol 2017 ◽  
pp. 1-9 ◽  
Author(s):  
Shataakshi Dube ◽  
Tejasvi Matam ◽  
Jessica Yen ◽  
Henry E. Mang ◽  
Pierre C. Dagher ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Ischemia Reperfusion Injury ◽  
Leukocyte Adhesion ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Organ Injury ◽  
Mrna Levels ◽  
Kidney Dysfunction ◽  
Stat3 Signaling ◽  
Proximal Tubular

STAT3 is a transcriptional regulator that plays an important role in coordinating inflammation and immunity. In addition, there is a growing appreciation of the role STAT3 signaling plays in response to organ injury following diverse insults. Acute kidney injury (AKI) from ischemia-reperfusion injury is a common clinical entity with devastating consequences, and the recognition that endothelial alterations contribute to kidney dysfunction in this setting is of growing interest. Consequently, we used a mouse with a genetic deletion of Stat3 restricted to the endothelium to examine the role of STAT3 signaling in the pathophysiology of ischemic AKI. In a mouse model of ischemic AKI, the loss of endothelial STAT3 signaling significantly exacerbated kidney dysfunction, morphologic injury, and proximal tubular oxidative stress. The increased severity of ischemic AKI was associated with more robust endothelial-leukocyte adhesion and increased tissue accumulation of F4/80+ macrophages. Moreover, important proximal tubular adaptive mechanisms to injury were diminished in association with decreased tissue mRNA levels of the epithelial cell survival cytokine IL-22. In aggregate, these findings suggest that the endothelial STAT3 signaling plays an important role in limiting kidney dysfunction in ischemic AKI and that selective pharmacologic activation of endothelial STAT3 signaling could serve as a potential therapeutic target.

scholarly journals Blood and urinary cytokine balance and renal outcomes at cardiac surgery

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
William T. McBride ◽  
Mary Jo Kurth ◽  
Anna Domanska ◽  
Joanne Watt ◽  
Gavin McLean ◽  
...  
Keyword(s):  
Cardiac Surgery ◽  
Inflammatory Cytokines ◽  
Clinical Utility ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Inflammatory Biomarkers ◽  
Cytokine Balance ◽  
Anti Inflammatory ◽  
Renal Hypoperfusion

Abstract Background Increased perioperative pro-inflammatory biomarkers, renal hypoperfusion and ischemia reperfusion injury (IRI) heighten cardiac surgery acute kidney injury (CS-AKI) risk. Increased urinary anti-inflammatory cytokines attenuate risk. We evaluated whether blood and urinary anti-inflammatory biomarkers, when expressed as ratios with biomarkers of inflammation, hypoperfusion and IRI are increased in CS-AKI patients. Methods Preoperative and 24-h postoperative blood and urinary pro-inflammatory and anti-inflammatory cytokines, blood VEGF and H-FABP (hypoperfusion biomarkers), and MK, a biomarker for IRI, were measured in 401 cardiac surgery patients. Pre- and postoperative concentrations of biomarkers and selected ratios thereof, were compared between non-CS-AKI and CS-AKI patients. Results Compared with non-CS-AKI, blood pro-inflammatory (pre- and post-op TNFα, IP-10, IL-12p40, MIP-1α, NGAL; pre-op IL-6; post-op IL-8, MK) and anti-inflammatory (pre- and post-op sTNFsr1, sTNFsr2, IL-1RA) biomarkers together with urinary pro-inflammatory (pre- and post-op uIL-12p40; post-op uIP-10, uNGAL) and anti-inflammatory (pre- and post-op usTNFsr1, usTNFsr2, uIL-1RA) biomarkers, were significantly higher in CS-AKI patients. Urinary anti-inflammatory biomarkers, when expressed as ratios with biomarkers of inflammation (blood and urine), hypoperfusion (blood H-FABP and VEGF) and IRI (blood MK) were decreased in CS-AKI. In contrast, blood anti-inflammatory biomarkers expressed as similar ratios with blood biomarkers were increased in CS-AKI. Conclusions The urinary anti-inflammatory response may protect against the injurious effects of perioperative inflammation, hypoperfusion and IRI. These finding may have clinical utility in bioprediction and earlier diagnosis of CS-AKI and informing future therapeutic strategies for CS-AKI patients.

Sign in / Sign up

Export Citation Format

Share Document