scholarly journals DNA demethylase Tet2 suppresses cisplatin-induced acute kidney injury

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Yinwu Bao ◽  
Mengqiu Bai ◽  
Huanhuan Zhu ◽  
Yuan Yuan ◽  
Ying Wang ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Signaling Pathway ◽  
Cell Injury ◽  
Inflammatory Responses ◽  
Kidney Injury ◽  
Renal Tissue ◽  
Clinical Samples ◽  
Mice Model ◽  
Expression Levels ◽  
Ppar Signaling

AbstractDemethylase Tet2 plays a vital role in the immune response. Acute kidney injury (AKI) initiation and maintenance phases are marked by inflammatory responses and leukocyte recruitment in endothelial and tubular cell injury processes. However, the role of Tet2 in AKI is poorly defined. Our study determined the degree of renal tissue damage associated with Tet2 gene expression levels in a cisplatin-induced AKI mice model. Tet2-knockout (KO) mice with cisplatin treatment experienced severe tubular necrosis and dilatation, inflammation, and AKI markers’ expression levels than the wild-type mice. In addition, the administration of Tet2 plasmid protected Tet2-KO mice from cisplatin-induced nephrotoxicity, but not Tet2-catalytic-dead mutant. Tet2 KO was associated with a change in metabolic pathways like retinol, arachidonic acid, linolenic acid metabolism, and PPAR signaling pathway in the cisplatin-induced mice model. Tet2 expression is also downregulated in other AKI mice models and clinical samples. Thus, our results indicate that Tet2 has a renal protective effect during AKI by regulating metabolic and inflammatory responses through the PPAR signaling pathway.

Oleanolic acid derivative isolated from Gardenia jasminoides var. radicans alleviates LPS-induced acute kidney injury in mice by reducing oxidative stress and inflammatory responses via the TLR4/NF-κB/NLRP3 signaling pathway

2020 ◽  
Vol 44 (5) ◽  
pp. 2091-2101
Author(s):  
Mengnan Zeng ◽  
Yangang Cao ◽  
Ruiqi Xu ◽  
Yuanyuan Wu ◽  
Yangyang Wang ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Acute Kidney Injury ◽  
Signaling Pathway ◽  
Acid Derivative ◽  
Oleanolic Acid ◽  
Inflammatory Responses ◽  
Kidney Injury ◽  
Gardenia Jasminoides ◽  
And Oxidative Stress ◽  
Oleanolic Acid Derivative

Acute kidney injury (AKI) is a frequent complication of sepsis with hallmarks including inflammation and oxidative stress.

scholarly journals IGF-1 Deficiency Rescue and Intracellular Calcium Blockade Improves Survival and Corresponding Mechanisms in a Mouse Model of Acute Kidney Injury

2020 ◽  
Vol 21 (11) ◽  
pp. 4095
Author(s):  
Samiksha Wasnik ◽  
Xiaolei Tang ◽  
Hongzheng Bi ◽  
Amir Abdipour ◽  
Edmundo E. Carreon ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Cell Injury ◽  
Combined Therapy ◽  
Kidney Injury ◽  
Cytosolic Calcium ◽  
Renal Tissue ◽  
Sublethal Dose ◽  
Gene Expression Response ◽  
Vascular Integrity

This study was undertaken to test two therapies for acute kidney injury (AKI) prevention, IGF-1, which is renal protective, and BTP-2, which is a calcium entry (SOCE) inhibitor. We utilized lipopolysaccharide (LPS) IP, as a systemic model of AKI and studied in five groups of animals. Three experiments showed that at 7 days: (1) LPS significantly reduced serum IGF-1 and intramuscular IGF-I in vivo gene therapy rescued this deficiency. (2) Next, at the 7-day time point, our combination therapy, compared to the untreated group, caused a significant increase in survival, which was noteworthy because all of the untreated animals died in 72 h. (3) The four pathways associated with inflammation, including (A) increase in cytosolic calcium, (B) elaboration of proinflammatory cytokines, (C) impairment of vascular integrity, and (D) cell injury, were adversely affected in renal tissue by LPS, using a sublethal dose of LPS. The expression of several genes was measured in each of the above pathways. The combined therapy of IGF-1 and BTP-2 caused a favorable gene expression response in all four pathways. Our current study was an AKI study, but these pathways are also involved in other types of severe inflammation, including sepsis, acute respiratory distress syndrome, and probably severe coronavirus infection.

scholarly journals Endothelial progenitor cells-derived exosomal microRNA-21-5p alleviates sepsis-induced acute kidney injury by inhibiting RUNX1 expression

2021 ◽  
Vol 12 (4) ◽  
Author(s):  
Yue Zhang ◽  
Hongdong Huang ◽  
Wenhu Liu ◽  
Sha Liu ◽  
Xue Yan Wang ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Progenitor Cells ◽  
Endothelial Progenitor Cells ◽  
Cecal Ligation ◽  
Kidney Injury ◽  
Renal Tissue ◽  
Endothelial Glycocalyx ◽  
Endothelial Progenitor ◽  
Marker Proteins ◽  
Related Transcription Factor

AbstractThe role of microRNA-21-5p (miR-21-5p) in sepsis-induced acute kidney injury (AKI) has been seldom discussed. Therefore, the objective of this present study was to investigate the mechanism of endothelial progenitor cells-derived exosomes (EPCs-exos) in sepsis-induced AKI via miR-21-5p/runt-related transcription factor 1 (RUNX1) axis. miR-21-5p was downregulated and RUNX1 was upregulated in the kidney of cecal ligation and puncture (CLP) rats, and miR-21-5p targeted RUNX1. Elevation of miR-21-5p improved renal function and renal tissue pathological damage, attenuated serum inflammatory response, as well as reduced apoptosis and oxidative stress response in renal tissues, and regulated endothelial glycocalyx damage marker proteins syndecan-1 and heparanase-1 in CLP rats. Overexpression of RUNX1 abolished the impacts of elevated miR-21-5p in CLP rats. Also, EPCs-exos upregulated miR-21-5p expression, and functioned similar to elevation of miR-21-5p for CLP rats. Downregulating miR-21-5p partially reversed the effects of EPCs-exos on sepsis-induced AKI. Collectively, our study suggests that EPCs release miR-21-5p-containing exosomes to alleviate sepsis-induced AKI through RUNX1 silencing.

scholarly journals NEAT1 aggravates sepsis-induced acute kidney injury by sponging miR-22-3p

Open Medicine ◽  
2020 ◽  
Vol 15 (1) ◽  
pp. 333-342
Author(s):  
Yawei Feng ◽  
Jun Liu ◽  
Ranliang Wu ◽  
Peng Yang ◽  
Zhiqiang Ye ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Western Blot ◽  
Cell Apoptosis ◽  
Noncoding Rna ◽  
Cell Injury ◽  
Kidney Injury ◽  
Inflammatory Factors ◽  
Luciferase Reporter ◽  
Enzyme Linked Immunosorbent Assay ◽  
Western Blot Assay

AbstractBackground and aimAcute kidney injury (AKI) is a common complication of sepsis. Long noncoding RNA nuclear-enriched abundant transcript 1 (NEAT1) plays a vital role in various diseases, including AKI. This study aimed to investigate the function and mechanism of NEAT1 in sepsis-induced AKI.Materials and methodsA septic AKI model was established by treating HK-2 cells with lipopolysaccharide (LPS). The levels of NEAT1 and miR-22-3p were measured by quantitative real-time PCR. Cell apoptosis was assessed by flow cytometry. The levels of apoptosis-related protein and autophagy-related factors were examined by the western blot assay. An enzyme-linked immunosorbent assay was used to calculate the contents of inflammatory factors. The interaction between NEAT1 and miR-22-3p was validated by dual-luciferase reporter assay, RNA immunoprecipitation assay, and RNA pull-down assay. The levels of nuclear factor (NF)-κB pathway-related proteins were evaluated by the western blot assay.ResultsNEAT1 was upregulated, while miR-22-3p was downregulated in patients with sepsis and in LPS-stimulated HK-2 cells. LPS treatment triggered cell apoptosis, autophagy, and inflammatory response in HK-2 cells. NEAT1 knockdown attenuated LPS-induced cell injury. NEAT1 modulated LPS-triggered cell injury by targeting miR-22-3p. Furthermore, NEAT1 regulated the NF-κB pathway by modulating miR-22-3p.ConclusionDepletion of NEAT1 alleviated sepsis-induced AKI via regulating the miR-22-3p/NF-κB pathway.

scholarly journals Gene Microarray Integrated with High-Throughput Proteomics for the Discovery of Transthyretin in Rhabdomyolysis-Induced Acute Kidney Injury

2017 ◽  
Vol 43 (4) ◽  
pp. 1673-1688 ◽  
Author(s):  
Ou Li ◽  
Xiaodong Geng ◽  
Qian Ma ◽  
Weiwei Wang ◽  
Ran Liu ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Western Blotting ◽  
Kidney Injury ◽  
Physical Exertion ◽  
Renal Tissue ◽  
Gene Microarray ◽  
Absolute Quantitation ◽  
Gene And Protein Expression ◽  
Isobaric Tagging

Background/Aims: Rhabdomyolysis, one of the leading causes of acute kidney injury (AKI), develops after trauma, drug toxicity, infections, burns, and physical exertion. The aim of this study was to investigate differences in gene and protein expression to elucidate the pathogenesis of rhabdomyolysis (RM)-induced AKI. Methods: In this study, we used glycerol induced renal injury as a model of RM-induced AKI. Affymetrix U133 plus 2.0 microarrays were used to perform gene microarray analysis. Isobaric tagging with related and absolute quantitation (iTRAQ) labeling mass spectrometry (MS) was applied to screen and identify differentially expressed proteins between RM-induced AKI and normal murine renal tissue. Verification experiments included immunohistochemistry (IHC), real-time PCR, Western blotting, and the measurement of ATP and ROS production. HK-2 cells were incubated in vitro with ferrous myoglobin and pcDNA-TTR, followed by assays to detect cell proliferation, ROS and apoptosis. Results: According to gene microarray and iTRAQ-MS analysis, we screened 17 common elements. After multiple analyses, we selected transthyretin (TTR) as our focus and investigated TTR in the kidney. Verification experiments with IHC confirmed differential expression levels of TTR proteins. Furthermore, Western blotting showed a stepwise decrease in TTR in AKI renal tissues. Cell-based experiments showed that overexpression of TTR could improve HK-2 cell viability and inhibit apoptosis. TTR reduced apoptosis by decreasing the accumulation of reactive oxygen species (ROS). Conclusion: This study reports a possible mechanism for RM-induced AKI and suggests that reductions in TTR could increase the generation of ROS and induce apoptosis. TTR may be a potentially valuable target for RM-induced AKI.

MO343SERUM RESPONSE FACTOR, A NOVEL EARLY DIAGNOSTIC BIOMARKER OF ACUTE KIDNEY INJURY

2021 ◽  
Vol 36 (Supplement_1) ◽  
Author(s):  
Long Zhao ◽  
Yan Xu
Keyword(s):  
Acute Kidney Injury ◽  
Serum Response Factor ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Diagnostic Value ◽  
Renal Tissue ◽  
Response Factor ◽  
Diagnostic Biomarker ◽  
Renal Tubular ◽  
Early Diagnostic

Abstract Background and Aims Studies have shown that serum response factor (SRF) is increased in chronic kidney injury, such as diabetic nephropathy, hyperuricemic nephropathy and renal cell carcinoma. The objective is to explore the early diagnostic value of SRF in acute kidney injury (AKI). Method AKI-related microarray data were analyzed, and the expression and location of SRF were investigated in the early phase of AKI. Results Bioinformatics results demonstrated that SRF was dramatically elevated 2-4 h after ischemia/reperfusion (I/R) in mouse renal tissue. In I/R rats, SRF was mostly expressed and located in renal tubular epithelial cells (TECs). SRF started to increase at 1 h, peaked at 3-9 h and started to decrease at 12 h after I/R. The areas under the ROC curve of renal SRF mRNA, renal SRF protein, urinary SRF, serum SRF and serum creatinine (Scr) were 87.9%, 83.0%, 81.3%, 78.8%, 68.8%, respectively. Conclusion SRF is remarkably upregulated in early (before 24 h) AKI and can replace Scr as a potential new early diagnostic biomarker of AKI.

Complement C5 inhibition protects against hemolytic anemia and acute kidney injury in anthrax peptidoglycan-induced sepsis in baboons

2021 ◽  
Vol 118 (37) ◽  
pp. e2104347118
Author(s):  
Ravi Shankar Keshari ◽  
Narcis Ioan Popescu ◽  
Robert Silasi ◽  
Girija Regmi ◽  
Cristina Lupu ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Hemolytic Anemia ◽  
Complement Activation ◽  
Inflammatory Responses ◽  
Atypical Hemolytic Uremic Syndrome ◽  
Kidney Injury ◽  
Multiple Organ ◽  
Immune Recognition ◽  
Gram Positive ◽  
Terminal Complement

Late-stage anthrax infections are characterized by dysregulated immune responses and hematogenous spread of Bacillus anthracis, leading to extreme bacteremia, sepsis, multiple organ failure, and, ultimately, death. Despite the bacterium being nonhemolytic, some fulminant anthrax patients develop a secondary atypical hemolytic uremic syndrome (aHUS) through unknown mechanisms. We recapitulated the pathology in baboons challenged with cell wall peptidoglycan (PGN), a polymeric, pathogen-associated molecular pattern responsible for the hemostatic dysregulation in anthrax sepsis. Similar to aHUS anthrax patients, PGN induces an initial hematocrit elevation followed by progressive hemolytic anemia and associated renal failure. Etiologically, PGN induces erythrolysis through direct excessive activation of all three complement pathways. Blunting terminal complement activation with a C5 neutralizing peptide prevented the progressive deposition of membrane attack complexes on red blood cells (RBC) and subsequent intravascular hemolysis, heme cytotoxicity, and acute kidney injury. Importantly, C5 neutralization did not prevent immune recognition of PGN and shifted the systemic inflammatory responses, consistent with improved survival in sepsis. Whereas PGN-induced hemostatic dysregulation was unchanged, C5 inhibition augmented fibrinolysis and improved the thromboischemic resolution. Overall, our study identifies PGN-driven complement activation as the pathologic mechanism underlying hemolytic anemia in anthrax and likely other gram-positive infections in which PGN is abundantly represented. Neutralization of terminal complement reactions reduces the hemolytic uremic pathology induced by PGN and could alleviate heme cytotoxicity and its associated kidney failure in gram-positive infections.

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