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Nrf2-mediated chromatin activation of hyperosmotic response genes attenuates heat-induced renal injury [ChIP-seq]

ABSTRACT: The escalating frequency and duration of extreme weather events, driven by ongoing climate change, are heightening health hazards associated with heat stress. Heat stress can cause whole-body hyperosmolarity and increase risk of chronic kidney disease. Here, we confirmed Nrf2 as the core transcription factor for cellular resistance to hyperosmotic stress through drug screening. Meanwhile, we constructed a mouse model of renal injury caused by high temperature dehydration, genetic deletion of Nrf2 further increased the renal injury and fibrosis. The natural compound SFN, found in cruciferous plants, can be used to activate Nrf2 and alleviate kidney damage caused by high-temperature dehydration. Mechanistically, we performed hyperosmotic stress in kidney collecting duct cells, and through ATAC-seq and ChIP-seq analysis of multiple histone modifications, found that most of the hyperosmotic response genes changed their chromatin state after pharmacological activation of Nrf2. The activation of the chromatin state in hyperosmotic response genes enhances the binding affinity of Nfat5 following exposure to hyperosmotic stress. Together, activation of Nrf2 maintains the active chromatin state of hyperosmotic response genes. Under hyperosmotic stress, the core transcription factor Nfat5 efficiently activates gene expression, thereby assisting cells in resisting hyperosmotic stress. Additionally, activation of Nrf2 by SFN may serve as a potential therapeutic approach for preventing renal injury caused by high-temperature dehydration.

ORGANISM(S): Mus musculus

PROVIDER: GSE266022 | GEO | 2026/07/29

REPOSITORIES: GEO

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Nrf2-mediated chromatin activation of hyperosmotic response genes attenuates heat-induced renal injury [RNA-seq]

Project description:The escalating frequency and duration of extreme weather events, driven by ongoing climate change, are heightening health hazards associated with heat stress. Heat stress can cause whole-body hyperosmolarity and increase risk of chronic kidney disease. Here, we confirmed Nrf2 as the core transcription factor for cellular resistance to hyperosmotic stress through drug screening. Meanwhile, we constructed a mouse model of renal injury caused by high temperature dehydration, genetic deletion of Nrf2 further increased the renal injury and fibrosis. The natural compound SFN, found in cruciferous plants, can be used to activate Nrf2 and alleviate kidney damage caused by high-temperature dehydration. Mechanistically, we performed hyperosmotic stress in kidney collecting duct cells, and through ATAC-seq and ChIP-seq analysis of multiple histone modifications, found that most of the hyperosmotic response genes changed their chromatin state after pharmacological activation of Nrf2. The activation of the chromatin state in hyperosmotic response genes enhances the binding affinity of Nfat5 following exposure to hyperosmotic stress. Together, activation of Nrf2 maintains the active chromatin state of hyperosmotic response genes. Under hyperosmotic stress, the core transcription factor Nfat5 efficiently activates gene expression, thereby assisting cells in resisting hyperosmotic stress. Additionally, activation of Nrf2 by SFN may serve as a potential therapeutic approach for preventing renal injury caused by high-temperature dehydration.

2026-07-29 | GSE266023 | GEO

Nrf2-mediated chromatin activation of hyperosmotic response genes attenuates heat-induced renal injury [ATAC-seq]

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Segment specific loss of NFAT5 function in the kidneys

Project description:Nuclear factor of activated T-cells 5 (NFAT5) is a transcription factor known for its role in osmotic stress adaptation in the renal inner medulla, due to osmotic gradient that is generated between renal cortex and renal inner medulla. However, its broader implications in kidney injury and chronic kidney disease (CKD) are less understood. Here we used two different Cre deleter mice (Ksp1.3-Cre and Aqp2-Cre) to generate tubule segment and even cell type specific NFAT5 deficient mice in the principal cells of the collecting duct (CD) and in the distal nephron starting in the TAL up to the CD and performed extensive gene expression profiling. In both Nfat5 knockout models, we observed massive changes in gene expression pattern, with heightened inflammatory responses and renal injury, culminating in renal fibrosis. Interestingly, inflammatory responses and fibrosis were much more prominent in the Aqp2Cre+/-Nfat5fl/fl mice that lack NFAT5 only in the collecting duct. By analyzing gene expression in the medullary and cortical regions of the kidney separately, we confirmed that the loss of NFAT5 results in kidney injury that extends beyond hypertonic areas. The correlation between the levels of inflammatory response, injury severity, and fibrosis indicates that cytokines are key mediators of stress signals in the kidney. Thus, NFAT5 is essential not only for adapting to osmotic stress but also for regulating cytokine signaling.

2025-02-05 | GSE276474 | GEO

A kidney-protective mechanism via cellular oxidative stress reduction induced by CD5L protein [UUO_scRNAseq]

Project description:Chronic kidney disease (CKD) encompasses multiple pathogenic mechanisms manifested by inflammation, fibrosis, oxidative stress and cell death. We previously showed that circulating protein CD5L (or AIM) ameliorates acute kidney injury, so we explored its effect in a mouse model of unilateral ureteral obstruction (UUO)-induced renal fibrosis. Here, we show a unique kidney-protective pathway mediated by CD5L. CD5L is endocytosed into renal epithelial cells, where it reduces oxidative stress, decreasing cell injury and death. This effect is supported by both a cysteine-dependent direct antioxidant activity of CD5L and enhancement of Nrf2-associated antioxidant responses. In addition, our data suggest that suppression of sphingomyelinase activity and reduction of cellular ceramide may contribute, at least in part, to CD5L-associated augmentation of Nrf2 nuclear transport. These effects depend on the reactive cysteine residue on CD5L surface. Consistent with these findings, recombinant CD5L treatment in UUO mice reduces sphingomyelinase activity, activates Nrf2, and lowers oxidative stress, alleviating inflammation, fibrosis, and kidney injury. Our findings uncover a novel antioxidant pathway mediated by CD5L with potential implications for CKD-associated fibrotic mechanisms.

2026-05-26 | GSE324542 | GEO

A kidney-protective mechanism via cellular oxidative stress reduction induced by CD5L protein [HK2_bulk RNA-seq]

2026-05-26 | GSE324328 | GEO

A kidney-protective mechanism via cellular oxidative stress reduction induced by CD5L protein [UUO_bulk RNA-seq]

2026-05-26 | GSE324326 | GEO

Effect of hypertonicity on chromatin accessibility and contribution of NFAT5

Project description:Understanding the mechanisms underlying cell type-specific gene expression in the kidney is essential to elucidate renal function. Using the Assay for Transposase-Accessible Chromatin with high-throughput sequencing (ATAC-seq) we analyzed open chromatin structures and the involvement of epigenetic mechanisms in mediating gene expression differences between the renal cortex (CTX) and inner medulla (IM). We also examined the role of the nuclear factor of activated T cells 5 (NFAT5), a key regulator of hypertonicity. ATAC-seq analysis was performed on CTX and IM samples from both wild-type (WT) and NFAT5 knockout (KO) mice. This study revealed global differences in chromatin accessibility between renal CTX and IM and the impact of NFAT5 loss on open chromatin regions. Furthermore, spatial localization and NFAT5-promoted chromatin accessibility correlate with differential gene expression and altered promoter binding motif enrichment in CTX and IM. Our findings provide new insights into spatial and NFAT5-promoted transcriptional regulation in the kidney, and their importance for renal function and adaptation to osmotic stress.

2025-11-01 | GSE247097 | GEO

Identification of Novel NRF2-Regulated Genes by ChIPSeq

Project description:Cellular oxidative and electrophilic stress triggers a protective response in mammals regulated by NRF2 (nuclear factor (erythroid-derived) 2-like; NFE2L2) binding to DNA-regulatory sequences near stress responsive genes. Studies using Nrf2-deficient mice suggest that hundreds of genes may be regulated by NRF2. To identify human NRF2-regulated genes, we conducted ChIP-sequencing experiments in lymphoid cells treated with the dietary isothiocyanate, sulforaphane (SFN) and carried out follow-up biological experiments on candidates. We found 242 high-confidence, NRF2-bound genomic regions and 96% of these regions contained NRF2-regulatory sequence motifs. The majority of binding sites were near potential novel members of the NRF2 pathway. Validation of selected candidate genes using parallel ChIP techniques and in NRF2-silenced cell lines indicated that the expression of about two thirds of the candidates are likely to be directly NRF2-dependent including retinoid X receptor alpha (RXRA). NRF2 regulation of RXRAhas implications for response to retinoid treatments and adipogenesis. In mouse 3T3-L1 cells SFN treatment affected Rxra expression early in adipogenesis and knockdown of Nrf2 delayed Rxra expression, both leading to impaired adipogenesis. ChIP-Seq analysis of NRF2 binding sites in human lymphoblastoid cells treated with sulforaphane or vehicle

2012-06-18 | E-GEOD-37589 | biostudies-arrayexpress

Hypertonicity induced changes in gene expression in mpkCCD cells and the contribution of NFAT5 activity on these changes.

Project description:The corticomedullary osmotic gradient between renal cortex and medulla induces a specific spatial gene expression pattern. The factors that control these differences are not fully addressed. The hypertonic environment leads to activation of the nuclear factor of activated T-cells 5 (NFAT5), which regulates the expression of osmoprotective genes. While NFAT5 function under hypertonic conditions has been extensively studied, its contribution to basal gene 28 regulation remains incompletely understood. We used murine principal kidney cortical collecting duct (mpkCCD) cells and induced functional deletion of NFAT5 and performed gene expression profiling to identify genes that are differentially expressed under isotonic and hypertonic cell culture conditions. Hypertonic stress induced extensive transcriptional changes in control cells, which were markedly altered in NFAT5-deficient cells. Furthermore, the comparison of the mpkCCD transcriptomes with gene expression profiles from renal cortex and inner medulla of control and principal cell-specific NFAT5 knockout mice revealed partial overlap in hypertonicity-associated and NFAT5-dependent gene expression patterns. In both conditions, the expression of known NFAT5 target genes, like Aqp2 or Ranbp3l, was downregulated. These findings support the use of mpkCCD cells as a complementary model to study NFAT5-associated gene regulation under controlled in vitro conditions.

2026-06-25 | GSE326713 | GEO

Dehydration impaired normal renal development in infant mice

Project description:The kidney is a major organ in which fluid balance and waste excretion is regulated. To obtain mature functions of the kidney, normal renal developmental processes need to be preceded. Comprehensive genetic programs underlying renal development during prenatal life have been widely studied. However, postnatal renal development, from infancy to juvenile period, have not been studied yet. Here, we investigated if structural and functional kidney development was still undergoing in early life by analyzing renal transcriptional networks of infant (4 weeks old) and juvenile (7 weeks old) mice. We further examined the effects of dehydration on kidney development. Kidneys at 4 weeks and 7 weeks old showed significantly distinctive functional network of genes. Gene sets related to cell cycle regulators and immature glomerular barrier integrity (COL4A1, COL4A2) were enriched in infantile kidneys while genes associated with ion transport and drug metabolism (CYP450 family) were shown in juvenile kidneys. Dehydration during infancy suppressed renal growth by interrupting SHH signaling pathway which targets cell cycle regulators. Importantly, disruption of developmental program ultimately led to long-term alterations in renal filtration function, by causing a decline in glomerular filtration barrier integrity. Taken together, we provide meaningful perspectives of renal development in infancy which suggests molecular and physiological background why infants are more vulnerable to dehydration than adults. These results provide new insights into the systemic effects of dehydration on renal development and may propose possible markers for clinical application in pediatric dehydration.

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