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Comparison of the kidney transcriptome of 45 days old principal cell-specific Tsc1 knockout (Tsc1f/f/Aqp2 Cre) vs Wild-type (WT) mice.

ABSTRACT: Tuberous sclerosis complex is a genetic disorder that affects multiple organs. In the kidney, it presents as hamartomas and cysts. The epithelium of TSC renal cysts is primarily composed of A-intercalated cells. In these studies, we compared the renal transcriptomes of 45 days old principal cell-specific Tsc1 knockout (Tsc1f/f/Aqp2 Cre; Tsc1 KO) and WT mice.

ORGANISM(S): Mus musculus

PROVIDER: GSE311309 | GEO | 2026/02/18

REPOSITORIES: GEO

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Comparison of the kidney transcriptome of 28 days old principal cell-specific Tsc1 knockout (Tsc1f/f/Aqp2 Cre) vs wild-type (WT) mice

Project description:Tuberous sclerosis complex is a genetic disorder that affects multiple organs. In the kidney, it presents as hamartomas and cysts. The epithelium of TSC renal cysts is primarily composed of A-intercalated cells. In these studies, we compared the renal transcriptomes of 28 days old principal cell-specific Tsc1 knockout (Tsc1f/f/Aqp2 Cre; Tsc1 KO) and WT mice.

2026-02-18 | GSE311308 | GEO

Comparison of the kidney transcriptome of 45 days old principal cell-specific Tsc1 knockout (Tsc1f/f/Aqp2 Cre), 45 days old principal cell-specific Tsc1 knockout/Foxi1 knockout (Tsc1/Foxi1 dKO), and 45 days old WT mice

Project description:Tuberous sclerosis complex is a genetic disorder that affects multiple organs. In the kidney, it presents as hamartomas and cysts. The epithelium of TSC renal cysts is primarily composed of A-intercalated cells. The transcription factor FOXI1 is indispensable in the development of intercalated cells. The expression of Foxi1 mRNA is significantly upregulated in the kidneys of various mouse models of TSC. The simultaneous ablation of Tsc1 and Foxi1 prevents the formation of cysts in the kidneys of Tsc1 KO mice. In these studies, we compared the renal transcriptomes of 45 days old principal cell-specific Tsc1 knockout, Tsc1/Foxi1 double knockout, and WT mice.

2026-02-18 | GSE311307 | GEO

CREB-family transcription factors and vasopressin-mediated regulation of Aqp2 gene transcription

Project description:Water homeostasis is regulated by the peptide hormone arginine vasopressin (AVP), which promotes water reabsorption in the renal collecting duct. The regulation of Aqp2 gene transcription is a key mechanism through which AVP modulates water transport as disruption of this mechanism leads to water balance disorders. Therefore, an important goal is to understand the regulatory processes that control Aqp2 gene transcription. While CREB (CREB1) has been proposed as the primary transcription factor responsible for Aqp2 transcription, recent evidence challenges this view, suggesting that other CREB-like transcription factors, including ATF1 and CREM, may play a role. We employed the CRISPR/Cas9 gene-editing system to delete Atf1, Creb1, and Crem in mpkCCD cells, an immortalized collecting duct cell line. These cell lines were then exposed to the vasopressin analog dDAVP to assess the role of these transcription factors in regulating Aqp2 expression. Deletion of all three transcription factors (ATF1, CREB1, and CREM) led to a significant reduction in the vasopressin-induced upregulation of AQP2 protein, confirming their role in regulating Aqp2 expression. Rescue experiments in triple knockout cells showed that expressing any of the three transcription factors restored the response to vasopressin. RNA-seq data showed that Aqp2 mRNA levels mirrored changes in protein abundance, supporting the idea that these transcription factors affect Aqp2 transcription. Our findings demonstrate that ATF1, CREB1, and CREM have redundant roles in regulating Aqp2 transcription. Our results suggest that these transcription factors might regulate the expression of other unidentified transcription factors involved in Aqp2 regulation.

2025-06-25 | GSE291084 | GEO

GPR39 activation inhibits AQP2 trafficking and alters cytoskeletal organization

Project description:G protein-coupled receptor 39 (GPR39) is an orphan receptor that is highly expressed in renal collecting duct principal cells. GPR39 activation in vivo leads to reduced urinary concentration capacity. In this study, we utilized mpkCCD cells, a model of principal cells in the collecting duct, to examine the cell biological effects of GPR39 activation. Pharmacological activation of GPR39 with the synthetic agonist cpd1324 impaired vasopressin-mediated aquaporin-2 (AQP2) apical trafficking and reduced total AQP2 expression following long-term treatment, consistent with its known in vivo role. These effects were absent in GPR39 knockout cells. In addition, GPR39 activation altered apical membrane morphology, disrupted the tight junction network, and reduced cortical F-actin expression, suggesting a shift toward a dedifferentiated phenotype. GPR39 activation also increased glycolytic ATP production while reducing mitochondrial ATP output without affecting proliferation. RNA-seq analysis of acutely treated mpkCCD cells revealed upregulation of inflammatory and dedifferentiation-associated gene programs, including cytokines. These findings indicate that the role of GPR39 in principal cells goes beyond AQP2 regulation and imply that GPR39 functions as a negative regulator of epithelial differentiation, perhaps acting to coordinate metabolic and inflammatory responses to stress.

2026-01-20 | GSE312829 | GEO

Transcription profiling of mpkCCDc14 cells cloned into colonies with varying aquaporin 2 (AQP2) expression levels in the presence of vasopressin analogy dDAVP to identify transcripts responsible for cell-specific expression of AQP2

Project description:This series of microarray data contain transcript intensity of mpkCCD cells. Experiment Overall Design: The mpkCCDc14 cells were cloned into colonies with varying aquaporin 2 (AQP2) expression levels in the presence of vasopressin analogy dDAVP. Transcript profiling was done for the original cells and cell clones 2, 3, 9, 10, and 11. By studying transcripts that correlate with AQP2 mRNA levels among cell clones, the objective was to identify transcripts responsible for cell-specific expression of AQP2.

2009-01-31 | E-GEOD-13667 | biostudies-arrayexpress

Tsc1 and Vhl loss cooperates to drive renal cell carcinoma through augmenting HIF1 and NRF2 signaling pathways

Project description:Besides the truncal VHL mutations, ccRCC is characterized by upregulated MTOR signals from both preclinical and clinical studies. To understand how upregulated MTOR signals cooperate with VHL loss in promoting kidney tumorigenesis, we generated kidney-specific deletion of Vhl and Tsc1 (Vhl;Tsc1 cDKO) in mice. The mice showed decreased life span with maximal age of 11 weeks, bilateral polycystic kidney diseases from ~3 weeks and multifocal solid renal cell carcinoma with eosinophilic cytoplasm and grade 2-3 from 7 weeks old. The mouse tumors resemble histology of the human kidney tumors with VHL and TSC1 mutations. To understand the mechanism of how Tsc1 loss cooperates with Vhl loss in promoting tumorigenesis, we performed transcriptomic, metabolomic and immunohistochemical profilings of renal cortices from age-matched wild-type, Vhl or Tsc1 single knockout, and Vhl;Tsc1 cDKO mice. Tsc1 loss cooperates with Vhl loss by augmenting the HIF1 transcriptional output, as well as altering the glutamine/glutamate metabolism, urea cycle, glycogen metabolism, and activating NRF2 signaling pathways which reprogram the cells to counteract the high oxidative stress associated with the proliferation. Our study reports a ccRCC mouse model recapitulating human ccRCC with same genetic background, provides mechanistic insights concerning cooperation between upregulated mTORC1 signals and VHL loss, generates in vivo reagents for studying ccRCC, and implicates potential clinical values.

2022-05-01 | GSE131735 | GEO

Tuberous sclerosis complex renal lesion pleiotropy arises from multiple aberrant developmental processes

Project description:Tuberous sclerosis complex (TSC) is a multisystem tumor-forming disorder caused by loss of TSC1 or TSC2. Renal manifestations predominately include cysts and angiomyolipomas. Despite a well-described monogenic etiology, the cellular pathogenesis has remained elusive. Here, we report a novel genetically-engineered human renal organoid model which recapitulates pleiotropic features of TSC kidney disease in vitro and upon orthotopic xenotransplantation. We find that loss of TSC1/2 affects multiple developmental processes in the renal epithelial, stromal, and glial compartments. First, loss of TSC1/2 leads to an expanded stroma by favouring stromal cell fate acquisition and alters terminal stromal cell identity. Second, epithelial cells in the TSC1/2-/- organoids exhibit a rapamycin-insensitive epithelial-to-mesenchymal transition. Third, a melanocytic population forms exclusively in TSC1/2-/- organoids, branching from MITF+ Schwann cell precursors of a bona fide neural crest-to-Schwann cell differentiation trajectory. Together, these results illustrate the pleiotropic developmental consequences of biallelic inactivation of TSC1/2 and offer insight into the pathogenesis of TSC kidney lesions.

2022-07-05 | GSE182632 | GEO

Tsc1 promotes the differentiation of memory CD8+ T cells via orchestrating the transcriptional and metabolic programs

Project description:Memory CD8+ T cells are an essential component of protective immunity. Signaling via mechanistic target of rapamycin (mTOR) has been implicated in the regulation of the differentiation of effector and memory T cells. However, little is understood about the mechanisms that control mTOR activity, or the effector pathways regulated by mTOR, in this process. We describe here that tuberous sclerosis 1 (Tsc1), a regulator of mTOR signaling, plays a crucial role in promoting the differentiation and function of memory CD8+ T cells in response to Listeria monocytogenes infection. Mice with specific deletion of Tsc1 in antigen-experienced CD8+ T cells evoked normal effector responses, but were markedly impaired in the generation of memory T cells and their recall responses to antigen re-exposure in a cell-intrinsic manner. Tsc1 deficiency suppressed the generation of memory-precursor effector cells (MPECs) while promoting short-lived effector cell (SLEC) differentiation. Functional genomic analysis indicated that Tsc1 coordinated gene expression programs underlying immune function, transcriptional regulation and cell metabolism. Furthermore, Tsc1 deletion led to excessive mTORC1 activity and dysregulated cellular metabolism including glycolytic and oxidative metabolism. These findings establish a Tsc1-mediated checkpoint in linking immune signaling and cell metabolism to orchestrate memory CD8+ T cell development and function. We used microarrays to explore the gene expression profiles differentially expressed in OVA-specific CD8+ T-cells from wild-type (WT; Tsc1-fl/fl and cre-negative) and Tsc1-/- (Tsc1-fl/fl and Granzyme B-cre-positive) mice

2014-09-20 | E-GEOD-61591 | biostudies-arrayexpress

Transcriptomic analysis of adipocyte Tsc1 knockout mammary glands.

Project description:We report here the adipocyte-specific ablation of Tsc1 and its affects on lactation and mammary gland function. In this dataset, mammary glands from wild-type and adipocyte Tsc1 knockout mice were isolated during lactation and analysed by RNAseq. Deletion of Tsc1 is predicted to activate mTORC1 in both peripheral and mammary adipocytes. This study demonstrates that deletion of Tsc1 in adipocytes changes mammary gland histology, and function resulting in changes to breastmilk composition.

2021-05-28 | GSE175620 | GEO

Tuberous sclerosis complex 1 (Tsc1) enforces quiescence of naive T cells to promote immune homeostasis and function

Project description:The mechanisms that regulate T cell quiescence are poorly understood. We report that tuberous sclerosis complex 1 (Tsc1) establishes a quiescent program in naïve T cells by controlling cell size, cell cycle entry, and responses to T cell receptor stimulation. Loss of quiescence predisposed Tsc1-deficient T cells to apoptosis that depleted conventional T cells and invariant natural killer T cells. Loss of Tsc1 function dampened in vivo immune responses to bacterial infection. Tsc1-deficient T cells exhibited increased mTORC1 but diminished mTORC2 activities, with mTORC1 activation essential for the disruption of immune homeostasis. Therefore, Tsc1-dependent control of mTOR is crucial in establishing naïve T cell quiescence to facilitate adaptive immune function. Naïve CD4 and CD8 T cells from wild-type and Tsc1-deficient mice (in triplicates each group) were stimulated with or without TCR signaling. RNA was analyzed by microarrays. WT/KO for 0 and 4 hr for CD4 (triplicates), and WT/KO for 0 hr for CD8 (duplicates).

2011-07-11 | E-GEOD-29797 | biostudies-arrayexpress

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