Gpr97 exacerbates AKI via mediating Sema3A signaling
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE108195 | GEO | 2017/12/19
SECONDARY ACCESSION(S): PRJNA422800
REPOSITORIES: GEO
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Project description:Gpr97 exacerbates AKI via mediating Sema3A signaling
| PRJNA422800 | ENA
Project description:Background G protein-coupled receptors (GPCRs) participate in a variety of physiologic functions, and several GPCRs have critical physiologic and pathophysiologic roles in the regulation of renal function. We investigated the role of Gpr97, a newly identified member of the adhesion GPCR family, in AKI.Methods AKI was induced by ischemia-reperfusion or cisplatin treatment in Gpr97-deficient mice. We assessed renal injury in these models and in patients with acute tubular necrosis by histologic examination, and we conducted microarray analysis and in vitro assays to determine the molecular mechanisms of Gpr97 function.Results Gpr97 was upregulated in the kidneys from mice with AKI and patients with biopsy-proven acute tubular necrosis compared with healthy controls. In AKI models, Gpr97-deficient mice had significantly less renal injury and inflammation than wild-type mice. Gpr97 deficiency also attenuated the AKI-induced expression of semaphorin 3A (Sema3A), a potential early diagnostic biomarker of renal injury. In NRK-52E cells subjected to oxygen-glucose deprivation, siRNA-mediated knockdown of Gpr97 further increased the expression of survivin and phosphorylated STAT3 and reduced toll-like receptor 4 expression. Cotreatment with recombinant murine Sema3A protein counteracted these effects. Finally, additional in vivo and in vitro studies, including electrophoretic mobility shift assays and luciferase reporter assays, showed that Gpr97 deficiency attenuates ischemia-reperfusion-induced expression of the RNA-binding protein human antigen R, which post-transcriptionally regulates Sema3A expression.Conclusions Gpr97 is an important mediator of AKI, and pharmacologic targeting of Gpr97-mediated Sema3A signaling at multiple levels may provide a novel approach for the treatment of AKI.
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Project description:Microarray-based clustering analysis of miRNAs altered in IRI-AKI mouse kidney
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Project description:The aim of this study was to identify miRNAs that regulate AKI and develop their applications as diagnostic biomarkers and therapeutic agents. First, kidney tissues from two different AKI mouse models, namely, AKI induced by the administration of lipopolysaccharide (LPS) causing sepsis (LPS-AKI mice) and AKI induced by renal ischemia–reperfusion injury (IRI-AKI mice), were exhaustively screened for their changes of miRNA expression compared with that of control mice by microarray analysis.
2021-05-14 | GSE172039 | GEO
Project description:The aim of this study was to identify miRNAs that regulate AKI and develop their applications as diagnostic biomarkers and therapeutic agents. First, kidney tissues from two different AKI mouse models, namely, AKI induced by the administration of lipopolysaccharide (LPS) causing sepsis (LPS-AKI mice) and AKI induced by renal ischemia–reperfusion injury (IRI-AKI mice), were exhaustively screened for their changes of miRNA expression compared with that of control mice by microarray analysis.
2021-05-14 | GSE172038 | GEO
Project description:RNA-seq analysis of kidney samples from mice after ischemia-reperfusion injury (IRI) identified 1,109 genes with altered expression between mild (20 minutes) and severe (35 minutes) IRI groups. Among these, 974 genes were upregulated and 135 were downregulated in the severe group.
2024-11-21 | GSE281539 | GEO
Project description:Ischemic acute kidney injury (AKI), a complication that frequently occurs in hospital settings, is often associated with hemodynamic compromise, sepsis, cardiac surgery or exposure to nephrotoxicants. AKI is associated with immune cell infiltration into the kidney stroma, which causes acute tubular injury. Here, using a murine renal ischemic-reperfusion injury (IRI) model we show that intercalated cells (ICs) rapidly adopt a pro-inflammatory phenotype post IRI. During the early phase of AKI, we demonstrate that either blocking the pro-inflammatory P2Y14 receptor located on the apical membrane of ICs, or ablation of the gene encoding the P2Y14 receptor in ICs: 1) inhibits IRI-induced chemokine expression increase in ICs; 2) reduces neutrophil and monocyte renal infiltration; 3) reduces the extent of kidney dysfunction; and 4) attenuates proximal tubule (PT) damage. These observations indicate that the P2Y14 receptor participates in the very first inflammatory steps associated with ischemic AKI. In addition, we show that the concentration of the P2Y14 receptor ligand, uridine diphosphate-glucose (UDP-Glc), is higher in urine samples from intensive care unit patients who developed AKI when compared with urine from patients without AKI. In particular, we observed a strong correlation between UDP-Glc concentration and the development of AKI in cardiac surgery patients. Our study identifies the UDP-Glc/P2Y14 receptor axis as a potential target for the prevention and/or attenuation of ischemic-AKI.
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Project description:Peptidyl arginine deiminase-4 (PAD4) catalyzes the conversion of peptidylarginine residues to peptidylcitrulline. We have previously shown that kidney ischemia-reperfusion (I/R) injury increases renal proximal tubular PAD4 expression and activity. Furthermore, kidney PAD4 plays a critical role in ischemic acute kidney injury (AKI) by promoting renal tubular inflammation, neutrophil infiltration, and NF-?B activation. However, the mechanisms of PAD4-mediated renal tubular inflammation and NF-?B activation after I/R remain unclear. Here, we show that recombinant PAD4 preferentially citrullinates recombinant IKK? [also called NF-?B essential modulator (NEMO)] over recombinant IKK? or IKK?. Consistent with this finding, PAD4 citrullinated renal proximal tubular cell IKK? and promoted NF-?B activation via I?B? phosphorylation in vitro. NEMO inhibition with a selective NEMO-binding peptide attenuated PAD4-mediated proinflammatory cytokine mRNA induction in HK-2 cells. Moreover, NEMO inhibition did not affect proximal tubular cell survival, proliferation, or apoptosis, unlike global NF-?B inhibition. In vivo, NEMO-binding peptide treatment protected against ischemic AKI. Finally, NEMO-binding peptide attenuated recombinant PAD4-mediated exacerbation of ischemic AKI, renal tubular inflammation, and apoptosis. Taken together, our results show that PAD4 exacerbates ischemic AKI and inflammation by promoting renal tubular NF-?B activity and inflammation via NEMO citrullination. Targeting NEMO activation may serve as a potential therapy for this devastating clinical problem.
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Project description:Netrin-1 regulates cell survival and apoptosis by activation of its receptors, including UNC5B. However, the in vivo role of UNC5B in cell survival during cellular stress and tissue injury is unknown. We investigated the role of UNC5B in cell survival in response to stress using mice heterozygously expressing the UNC5B gene (UNC5B(-/flox)) and mice with targeted homozygous deletion of UNC5B in kidney epithelial cells (UNC5B(-/flox/GGT-cre)). Mice were subjected to two different models of organ injury: ischemia reperfusion injury of the kidney and cisplatin-induced nephrotoxicity. Both mouse models of UNC5B depletion had normal organ function and histology under basal conditions. After AKI, however, UNC5B(-/flox/GGT-cre) mice exhibited significantly worse renal function and damage, increased tubular apoptosis, enhanced p53 activation, and exacerbated inflammation compared with UNC5B(-/flox) and wild-type mice. shRNA-mediated suppression of UNC5B expression in cultured tubular epithelial cells exacerbated cisplatin-induced cell death in a p53-dependent manner and blunted Akt phosphorylation. Inhibition of PI3 kinase similarly exacerbated cisplatin-induced apoptosis; in contrast, overexpression of UNC5B reduced cisplatin-induced apoptosis in these cells. Taken together, these results show that the netrin-1 receptor UNC5B plays a critical role in cell survival and kidney injury through Akt-mediated inactivation of p53 in response to stress.
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Project description:Semophorin (SEMA) 6A showed capability to reduce the SEMA3A-derived supression of T cells. However, the effect of SEMA6A on the other immune cells was still unclear. Therefore, we performed gene expression analysis using an Affymetrix mouse genome 430 2.0 array to investigate the potential immune cells regualted by the interaction of SEMA6A and SEMA3A. Thus, we predicted other possible immune cells regulated by SEMA6A using GSEA to analyze the microarray data of co-cultured splenocytes. The reuslts revealed that SEMA6A decreased the SEMA3A-mediated inhibition of B cells and induced activities of dendritic cells in a SEMA3A-indepenet manner. Moreover, M1 and M2 macrophages were not influenced by SEMA6A and SEMA3A.
2020-04-16 | GSE148718 | GEO