Effects of GPX3-Specific Knockout in Renal Tubular Epithelial Cells on Kidney Gene Expression During the IRI-AKI Process
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ABSTRACT:
PROVIDER: PRJNA1195912 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR31749241_1.fastq.gz | Fastqsanger.gz | |||
| SRR31749241_2.fastq.gz | Fastqsanger.gz | |||
| SRR31749242_1.fastq.gz | Fastqsanger.gz | |||
| SRR31749242_2.fastq.gz | Fastqsanger.gz | |||
| SRR31749243_1.fastq.gz | Fastqsanger.gz |
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Project description:GPX3 is primarily synthesized and secreted by renal tubular epithelial cells and serves as the main source of GPX3 in plasma. A portion of GPX3 adheres to the renal basement membrane, suggesting that GPX3 may also regulate renal cell physiological functions. Our previous work has found that GPX3 expression is downregulated in the renal tubular epithelial cells of mice that have undergone ischemia-reperfusion-induced acute kidney injury, but the specific impact of this downregulation remains unclear. To address this, we constructed mice with specific deletion of GPX3 in renal tubular epithelial cells and subjected them to ischemia-reperfusion modeling. We reported the protective role of native GPX3 in the kidneys under IRI-AKI conditions in mitigating oxidative stress and mitochondrial damage in tubular epithelial cells. The deletion of GPX3 in tubular epithelial cells exacerbated oxidative stress, apoptosis, and mitochondrial dysfunction in IRI-AKI. Renal cortex tissue from control and IRI-modeled mice was used for RNA sequencing. Overall, our data provide an overview of the genetic changes in the kidneys of mice with GPX3 knockout in both non-modeled and IRI-AKI-modeled conditions, laying the groundwork for studying the specific mechanisms by which GPX3 regulates renal function.
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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.
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Project description:Acute kidney injury (AKI) have been thought to be reversible condition, however, emerging evidence demonstrated association between AKI and subsequent development of irreversible fibrosis and chronic kidney disease. In the present study, since recovery of AKI depends on renal tubular regeneration, factors expressing in renal tubules in adaptive or maladaptive repair process were investigated to predict reversibility of kidney injury. In the kidney of female F344 rats subjected to ischemia/reperfusion (I/R), regenerative tubules and dilated tubules were observed at 3 and 7 days after I/R. In fibrotic areas of the kidney of male SD rats subjected to I/R, renal tubules were dilated or atrophied. From microarray data of regenerative tubules, survivin, sex-determining region Y (SRY)-box 9 (SOX9), and CD44 were extracted as factors possibly relating to tubular regeneration or fibrosis. Immunohistochmical analysis demonstrated that survivin and SOX9 expressed in regenerative tubules, while SOX9 also expressed in renal tubules in fibrotic area, indicating that survivin and SOX9 contribute renal tubular regeneration, but sustained SOX9 expression may lead fibrosis. CD44 expressed in dilated tubules at day 3 and 7, and tubules in fibrotic area, suggesting that CD44 expressed in maladaptive tubules. These information will be helpful to consider reversibility of kidney injury.
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Project description:NF-κB is a key regulator of innate and adaptive immunity and is implicated in the pathogenesis of acute kidney injury (AKI). The cell type-specific functions of NF-κB in the kidney are unknown; however, the pathway serves distinct functions in immune and tissue-parenchymal cells. We analyzed tubular epithelial-specific NF-κB signaling in a mouse model of ischemia-reperfusion injury (IRI)-induced AKI. NF-κB reporter activity and nuclear localization of phosphorylated NF-κB subunit p65 analyses in mice revealed widespread NF-κB activation in renal tubular epithelia and in interstitial cells following IRI that peaked at 2-3 days after injury. To genetically antagonize tubular epithelial NF-κB activity, we generated mice expressing the human NF-κB super-repressor IκBα∆N in renal proximal, distal, and collecting duct epithelial cells. These mice were protected from IRI-induced AKI, as indicated by improved renal function, reduced tubular apoptosis, and attenuated neutrophil and macrophage infiltration. Tubular NF-κB-dependent gene expression profiles revealed temporally distinct functional gene clusters for apoptosis, chemotaxis, and morphogenesis. Primary proximal tubular cells isolated from IκBα∆N-expressing mice exposed to hypoxia-mimetic agent cobalt chloride were protected from apoptosis and expressed reduced levels of chemokines. Our results indicate that postischemic NF-κB activation in renal-tubular epithelia aggravates tubular injury and exacerbates a maladaptive inflammatory response.
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Project description:Acute kidney injury (AKI) is rapidly increasing and becomes a major of public health problem nowadays. However, its underlying mechanism has not been elucidated. Studies have shown that cluster of differentiation-44 (CD44) play a role in the pathological process of AKI. Nevertheless, the molecule mechanism has not been totally clarified. Herein, we found that CD44 is increased in renal tubules in ischemia-reperfusion injury (IRI)-induced AKI mice. Knockout of CD44 improved mitochondrial biogenesis and mitochondrial fatty acid oxidation (FAO), further protecting against renal tubular cell apoptosis and kidney injury. Conversely, ectopic expression of CD44 impaired mitochondrial function and FAO, which exacerbated the pathological process of AKI. Transcriptome sequencing revealed NF-κB p65 is highly responsible for this process. In vitro, we found that CD44 induced activation of NF-κB p65 via mitogen-activated protein kinase (MAPK) ERK1/2 and MAPK p38, further transcriptionally silencing peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) promoters. As a result, downregulation of PGC-1α contributed to impairment of mitochondrial dysfunction and FAO, resulting in the deterioration of AKI. Our study found that inhibiting CD44 is a new potential therapeutic strategy for AKI through promoting mitochondrial biogenesis and FAO. The underlying mechanism is associated with MAPK/p65/ PGC-1α pathway.
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Project description:Kidney damage involves the progressive and inexorable destruction of tubular and glomerular system. However, it is known that the patients survive AKI often recover renal structure and function. Correspondingly, previous studies demonstrated tubular regeneration in mice after massive kidney injury and linked mouse Sox9+ renal progenitor cells to this process. Here we show that renal progenitor cells can be cloned from renal needle biopsy sample of CKD patients. Progenitor cells can readily assembly into “kidney organoids” expressing proximal/distal tubular cell markers in 3D culture.
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