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Human Tubular Epithelial Cells Activate a Coordinated Stress Response after Serum Exposure [RNAseq-pid2019]

ABSTRACT: Proteinuria, the spillage of serum proteins into the urine, is a feature of glomerulonephritides, podocyte disorders and diabetic nephropathy. However, the response of tubular epithelial cells to serum protein exposure has not been systematically characterized. Using transcriptomic profiling we studied serum-induced changes in primary human tubular epithelial cells cultured in 3D microphysiological devices. Serum proteins induced cellular proliferation, secretion of cytokines and activated a coordinated stress response. We orthogonally confirmed our findings by comparing the transcriptomic and epigenomic landscapes of. Importantly, key transcriptomic programs in response to serum exposure remained consistent when comparing intact renal cortex to primary human tubules cultured in 10% fetal bovine serum and to an established mouse model of kidney injury. This serum-induced transcriptional response was dominated by AP-1 and NFkB signatures in the tubular epigenomic landscape with features of active regulation at canonical kidney injury genes (HAVCR1) and genes associated with COVID-19 (ACE2, IL6). Our data provide a reference map for dissecting the regulatory and transcriptional response of tubular epithelial cells to serum-induced injury.

ORGANISM(S): Homo sapiens

PROVIDER: GSE159586 | GEO | 2022/02/08

REPOSITORIES: GEO

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Human Tubular Epithelial Cells Activate a Coordinated Stress Response after Serum Exposure [RNAseq-pid1830]

Project description:Proteinuria, the spillage of serum proteins into the urine, is a feature of glomerulonephritides, podocyte disorders and diabetic nephropathy. However, the response of tubular epithelial cells to serum protein exposure has not been systematically characterized. Using transcriptomic profiling we studied serum-induced changes in primary human tubular epithelial cells cultured in 3D microphysiological devices. Serum proteins induced cellular proliferation, secretion of cytokines and activated a coordinated stress response. We orthogonally confirmed our findings by comparing the transcriptomic and epigenomic landscapes of. Importantly, key transcriptomic programs in response to serum exposure remained consistent when comparing intact renal cortex to primary human tubules cultured in 10% fetal bovine serum and to an established mouse model of kidney injury. This serum-induced transcriptional response was dominated by AP-1 and NFkB signatures in the tubular epigenomic landscape with features of active regulation at canonical kidney injury genes (HAVCR1) and genes associated with COVID-19 (ACE2, IL6). Our data provide a reference map for dissecting the regulatory and transcriptional response of tubular epithelial cells to serum-induced injury.

2022-02-08 | GSE159554 | GEO

Remote ischemic preconditioning causes transient cell-cycle arrest and renal protection by a NF-kB-dependent Sema5B pathway

Project description:Our study investigates how RIPC modulates the transcriptomic profile of neutrophils and renal tubular epithelial cells in the kidney during acute kidney injury.

2022-06-16 | GSE206091 | GEO

Glutamine attenuates renal ischemia-reperfusion injury and prevents acute kidney damage

Project description:Our study investigates how the systemic administration of glutamine modulates the transcriptomic profile of neutrophils and renal tubular epithelial cells in the kidney during acute kidney injury.

2021-11-13 | GSE188628 | GEO

Tubular epithelial NF-κB activity regulates acute ischemic kideny injury [OTT-211009]

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.

2016-09-17 | GSE87024 | GEO

Tubular epithelial NF-κB activity regulates acute ischemic kideny injury [130402-EV-EmxdN]

2016-09-17 | GSE87023 | GEO

Streptozotocin induces renal proximal tubular injury through p53 signaling activation

Project description:Streptozotocin (STZ) is an anti-cancer drug that is primarily used to treat neuroendocrine tumors (NETs) in clinical settings and develop type 1 diabetes rodent models in experimental fields. STZ is incorporated into cells through the glucose transporter, GLUT2, which is primarily expressed in pancreatic β-cells or proximal tubular epithelial cells in the kidney. However, its cytotoxic effects on kidney cells have been underestimated and the underlying mechanisms remain unclear. We herein demonstrated that DNA damage and subsequent p53 signaling were responsible for the development of STZ-induced tubular epithelial injury. We detected tubular epithelial DNA damage in NET patients treated with STZ. Unbiased transcriptomics of tubular epithelial cells in vitro showed the activation of the p53 signaling pathway by STZ. STZ induced DNA damage and activated p53 signaling in vivo in a dose-dependent manner, resulting in reduced membrane transport. The localization of STZ-induced kidney injury was limited to within the kidney cortex, which was independent of blood glucose. The pharmacological inhibition of p53 and sodium-glucose transporter 2 (SGLT2) mitigated STZ-induced epithelial injury. However, the cytotoxic effects of STZ on pancreatic β-cells were preserved in SGLT2 inhibitor-treated mice. The present results demonstrate the strong proximal tubular-specific cytotoxicity of STZ and the underlying mechanisms in vivo, which may be ameliorated by a SGLT2 inhibitor pretreatment. Since the cytotoxic effects of STZ against β-cells were not impaired by dapagliflozin, a pretreatment with a SGLT2 inhibitor has potential as a preventative remedy for kidney injury in NET patients treated with STZ.

2023-06-07 | GSE215337 | GEO

Glutamine attenuates renal ischemia-reperfusion injury and prevents acute kidney damage

Project description:Acute kidney injury (AKI) represents a common complication in critically ill patients that is associated with an increased morbidity and mortality. Currently, no effective treatment options are available. Here, we show that glutamine significantly attenuates leukocyte recruitment and inflammatory signaling in human and murine tubular epithelial cells (TECs). In a murine AKI model induced by ischemia-reperfusion-injury (IRI) we show that glutamine causes transcriptomic and proteomic reprogramming in renal TECs and neutrophils, resulting in decreased epithelial apoptosis, neutrophil recruitment and improved mitochondrial functionality and respiration provoked by an ameliorated oxidative phosphorylation. We identify the proteins glutamine gamma glutamyltransferase 2 (Tgm2) and apoptosis signal-regulating kinase (Ask1) as the major targets of glutamine in apoptotic signaling. Increased Tgm2 expression and reduced Ask1 activation result in decreased JNK activation leading to a diminished mitochondrial intrinsic apoptosis in kidneys upon IRI-induced AKI and under hypoxia or following TNFα-treatment of TECs. Consequently, glutamine administration attenuated kidney injury in vivo during AKI progression as well as TEC viability in vitro under inflammatory and hypoxic conditions.

2023-03-11 | PXD029723 | Pride

Granulosa cell-derived serum TNF-α mediates inflammation and apoptosis in renal tubular cells through NF-κB signaling and indicates PCOS-related kidney injury.

Project description:Serum TNF-α plays a key role in mediating inflammation and apoptosis in renal tubular cells and indicates PCOS-related kidney injury.

2023-12-06 | GSE229106 | GEO

CD47 modulates the interaction of γ-catenin with E-cadherin and participates in epithelial–mesenchymal transformation in lipid nephrotoxicity

Project description:Hyperlipidemia, an important risk factor for cardiovascular diseases and end-stage renal disease, often increases renal injury and compromises kidney function. In the present study, the kidney histology analysis in human samples showed that high lipid levels induced renal fibrosis. However, the mechanism of lipid nephrotoxicity remains unknown. We employed mice models of two kinds to further experiments. The kidney histology analysis in mouse showed that high lipid levels induced renal fibrosis that was further confirmed by Western blot and real-time PCR of fibrotic indexes (fibronection, collagenI and α-SMA). In Vitro analysis also supported that OX-LDL significantly induced fibrotic response in HK-2 tubular epithelial cells. To further ascertain the mechanism of high lipid-induced fibrosis, RNA-sequencing (RNA-Seq) was performed. Combined the Gene Ontology (GO) analysis results of differentially expressed mRNAs obtained by RNA-Seq with the results of LC-MS/MS and STRING Functional Association Networks showed that CD47 modulated the interaction of γ-catenin with E-cadherin and participated in epithelial–mesenchymal transformation in lipid nephrotoxicity. The inhibition of CD47 expression by transfected with shRNA plasmid or treated with anti-CD47 antibody in OX-LDL-treated tubular epithelial cells restored the expression of E-cadherin and attenuated renal injury including fibrosis and inflammatory response. These findings indicate that CD47 may be a therapeutic potential target for long-term lipid abuse-induced kidney injury.

2021-03-10 | GSE161737 | GEO

Activation of the YAP/KLF5 transcriptional cascade in renal tubular cells aggravates kidney injury

Project description:The Hippo/YAP pathway plays a critical role in early embryonic kidney development, but its functions in the adult kidney are less well understood. Our previous work has demonstrated that tubular YAP activation induced by double knockout of the upstream Hippo kinases Mst1 and Mst2 (Mst1/2 dKO) promotes tubular injury and renal inflammation under basal conditions. However, the importance of tubular YAP activation remains to be established in injured kidneys in which many other injurious pathways are simultaneously activated. Several secreted factors were found to be increased by YAP in tubular cells, but how the transcriptional network is altered by YAP is largely unknown. Here, we show that tubular YAP was already activated at 6 h after unilateral ureteral obstruction (UUO). Tubular YAP deficiency greatly attenuated tubular cell over-proliferation, tubular injury and renal inflammation induced by UUO or cisplatin. RNA-Seq, ChIP and luciferase assay revealed that YAP promoted the transcription of the transcription factor KLF5 whereas no interaction between YAP and KLF5 was observed. Consistently, the elevated expression of KLF5 and its target genes in Mst1/2 dKO or UUO kidneys was blocked by ablation of Yap in tubular cells. Inhibition of KLF5 prevented tubular cell over-proliferation, tubular injury and renal inflammation in Mst1/2 dKO kidneys. Therefore, our results demonstrate that tubular YAP is a key player in kidney injury. YAP and KLF5 form a transcriptional cascade, in which tubular YAP activation induced by kidney injury promotes KLF5 transcription. Activation of this cascade induces tubular cell over-proliferation, tubular injury and renal inflammation

2024-05-01 | GSE235443 | GEO

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