Renal tubular Pck1 knockout mice showed albuminuria.
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ABSTRACT:
PROVIDER: PRJNA947941 | ENA |
REPOSITORIES: ENA
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Project description:We aim to investigate the role of renal Pck1 on albuminuria. To further development of our gene expression approach to biodosimetry, we have employed whole genome microarray expression profiling as a discovery platform to identify genes with the potential to distinguish between wild type mice. To elucidate the molecular mechanisms underlying the increase in albuminuria by our Pck-CKO (Pck1 conditional knockout) mice, we performed DNA microarray analysis using whole kidneys to examine the differences in gene expression between Pck1-CKO and wild-type control mice.
2023-03-29 | GSE228053 | GEO
Project description:Metabolic alterations are recognized as key features of kidney injury, but their causal role in kidney repair remains a topic of debate. We investigate the role of PCK1, an enzyme involved in gluconeogenesis and cataplerosis, i.e. the removal of TCA intermediates from the mitochondrial matrix, in kidney disease. We demonstrate that PCK1 loss leads to injured mitochondria with decreased respiration and TCA metabolites accumulation. This results in inflammation, tubular injury and impaired tubule repair. We show that maintaining PCK1 expression in models of acute and chronic kidney disease preserves renal structure and function by improving TCA metabolite clearance. Restoration of PCK1 enhances mitochondrial health, reducing the progression to fibrosis. In humans, we confirm the correlation between PCK1 loss, mitochondrial injury as well as a failed tubule repair phenotype. We further observe the accumulation of TCA metabolites consistent with disrupted cataplerosis in chronic kidney disease. Our findings establish the maintenance of cataplerosis as an important factor of tubular physiology and repair and PCK1 as causal and potential therapeutic targets in this process.
2025-06-18 | GSE280120 | GEO
Project description:Metabolic alterations are recognized as key features of kidney injury, but their causal role in kidney repair remains a topic of debate. We investigate the role of PCK1, an enzyme involved in gluconeogenesis and cataplerosis, i.e. the removal of TCA intermediates from the mitochondrial matrix, in kidney disease. We demonstrate that PCK1 loss leads to injured mitochondria with decreased respiration and TCA metabolites accumulation. This results in inflammation, tubular injury and impaired tubule repair. We show that maintaining PCK1 expression in models of acute and chronic kidney disease preserves renal structure and function by improving TCA metabolite clearance. Restoration of PCK1 enhances mitochondrial health, reducing the progression to fibrosis. In humans, we confirm the correlation between PCK1 loss, mitochondrial injury as well as a failed tubule repair phenotype. We further observe the accumulation of TCA metabolites consistent with disrupted cataplerosis in chronic kidney disease. Our findings establish the maintenance of cataplerosis as an important factor of tubular physiology and repair and PCK1 as causal and potential therapeutic targets in this process.
2025-06-18 | GSE280119 | GEO
Project description:Metabolic alterations are recognized as key features of kidney injury, but their causal role in kidney repair remains a topic of debate. We investigate the role of PCK1, an enzyme involved in gluconeogenesis and cataplerosis, i.e. the removal of TCA intermediates from the mitochondrial matrix, in kidney disease. We demonstrate that PCK1 loss leads to injured mitochondria with decreased respiration and TCA metabolites accumulation. This results in inflammation, tubular injury and impaired tubule repair. We show that maintaining PCK1 expression in models of acute and chronic kidney disease preserves renal structure and function by improving TCA metabolite clearance. Restoration of PCK1 enhances mitochondrial health, reducing the progression to fibrosis. In humans, we confirm the correlation between PCK1 loss, mitochondrial injury as well as a failed tubule repair phenotype. We further observe the accumulation of TCA metabolites consistent with disrupted cataplerosis in chronic kidney disease. Our findings establish the maintenance of cataplerosis as an important factor of tubular physiology and repair and PCK1 as causal and potential therapeutic targets in this process.
2025-06-18 | GSE280118 | GEO
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.
2022-04-22 | GSE119426 | GEO
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.
2025-03-17 | GSE283852 | GEO
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 progenitor cells can be cloned from mouse medulla and cortex. Clones can be grown from a single cell and indefinitely passaged. Progenitor cells derived from renal medulla can readily assembly into “kidney organoids” expressing proximal/distal tubular cell markers in 3D culture.
2022-04-22 | GSE120049 | GEO
Project description:The mechanistic target of rapamycin mTORC1 is a key regulator of cell metabolism and autophagy. Despite widespread clinical use of mTOR inhibitors, the role of mTORC1 in renal tubular function and kidney homeostasis remains elusive. By utilizing constitutive and inducible deletion of conditional Raptor alleles in renal tubular epithelial cells, we discovered that mTORC1 deficiency caused a marked concentrating defect, loss of tubular cells and slowly progressive renal fibrosis. Transcriptional profiling revealed that mTORC1 maintains renal tubular homeostasis by controlling mitochondrial metabolism and biogenesis as well as transcellular transport processes involved in counter-current multiplication and urine concentration. Although mTORC2 partially compensated the loss of mTORC1, exposure to ischemia and reperfusion injury exaggerated the tubular damage in mTORC1-deficient mice, and caused pronounced apoptosis, diminished proliferation rates and delayed recovery. These findings identify mTORC1 as an essential regulator of tubular energy metabolism and as a crucial component of ischemic stress responses. Pharmacological inhibition of mTORC1 likely affects tubular homeostasis, and may be particularly deleterious if the kidney is exposed to acute injury. Furthermore, the combined inhibition of mTORC1 and mTORC2 may increase the susceptibility to renal damage. Raptor fl/fl*KspCre and Raptor fl/fl animals were sacrificed at P14 before the development of an overt functional phenotype. Kidneys were split in half and immediately snap frozen in liquid nitrogen.
2014-06-09 | E-GEOD-54417 | biostudies-arrayexpress
Project description:Diabetic nephropathy is considered one of the most common microvascular complications of diabetes and the pathophysiology involves multiple factors. Progressive diabetic nephropathy is believed to be related to the structure and function of the tubular epithelial cells in the kidney. However, the role of lysine acetylation in lesions of the renal tubular epithelial cells arising from hyperglycemia is poorly understood. Consequently, in this study, we cultured mouse renal tubular epithelial cells in vitro under high glucose conditions and analyzed the acetylation levels of proteins by liquid chromatography-high-resolution mass spectrometry. We identified 48 upregulated proteins and downregulated 86 proteins. In addition, we identified 113 sites with higher acetylation levels and 374 sites with lower acetylation levels. Subcellular localization analysis showed that the majority of the acetylated proteins were located in the mitochondria (43.17%), nucleus (28.57%) and cytoplasm (16.19%). Enrichment analysis indicated that these acetylated proteins are primarily associated with oxidative phosphorylation, the citrate cycle (TCA cycle), metabolic pathways and carbon metabolism. In addition, we used the MCODE plug-in and the cytoHubba plug-in in Cytoscape software to analyze the PPI network and displayed the first four most compact MOCDEs and the top 10 hub genes from the differentially expressed proteins between global and acetylated proteomes. Finally, we extracted 37 conserved motifs from 4915 acetylated peptides. Collectively, this comprehensive analysis of the proteome reveals novel insights into the role of lysine acetylation in tubular epithelial cells and may make a valuable contribution towards the identification of the pathological mechanisms of diabetic nephropathy.
2022-02-17 | PXD029651 | Pride
Project description:Diabetic kidney disease is a major complication in diabetes mellitus, and the most common reason for end-stage renal disease. Patients suffering from diabetes mellitus encounter glomerular damage by basement membrane thickening, and develop albuminuria. Subsequently, albuminuria can deteriorate the tubular function and impair the renal outcome. The impact of diabetic stress conditions on the metabolome was investigated by untargeted gas chromatography-mass spectrometry (GC-MS) analyses. The results were validated by qPCR analyses. In total, four cell lines were tested, representing the glomerulus, proximal nephron tubule, and collecting duct. Both murine and human cell lines were used. In podocytes, proximal tubular and collecting duct cells, high glucose concentrations led to global metabolic alterations in amino acid metabolism and the polyol pathway. Albumin overload led to the further activation of the latter pathway in human proximal tubular cells. In the proximal tubular cells, aldo-keto reductase was concordantly increased by glucose, and partially increased by albumin overload. Here, the combinatorial impact of two stressful agents in diabetes on the metabolome of kidney cells was investigated, revealing effects of glucose and albumin on polyol metabolism in human proximal tubular cells. This study shows the importance of including highly concentrated albumin in in vitro studies for mimicking diabetic kidney disease.
2019-10-08 | MTBLS1093 | MetaboLights