Transcriptomics of SGLT2-positive early proximal tubule segments in mice: response to type 1 diabetes, SGLT1/2 inhibition or GLP1 receptor agonism
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1171019 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR30939026_1.fastq.gz | Fastqsanger.gz | |||
| SRR30939026_2.fastq.gz | Fastqsanger.gz | |||
| SRR30939027_1.fastq.gz | Fastqsanger.gz | |||
| SRR30939027_2.fastq.gz | Fastqsanger.gz | |||
| SRR30939028_1.fastq.gz | Fastqsanger.gz |
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Project description:SGLT2 inhibitors (SGLT2i) and GLP1 receptor (GLP1R) agonists have kidney protective effects. To better understand their molecular effects, RNA sequencing was performed in SGLT2-positive proximal tubule segments isolated by immunostaining-guided laser capture microdissection. Male adult DBA wildtype (WT) and littermate diabetic Akita mice ± Sglt1 knockout (Sglt1-KO) were given vehicle or SGLT2i dapagliflozin (dapa; 10mg/kg diet) for 2 weeks, and other Akita mice received GLP1R agonist semaglutide (sema; 3nmol/[kg body weight*day], s.c.). Dapa (254±11mg/dL) and Sglt1-KO (367±11mg/dL) but not sema (407±44mg/dL) significantly reduced hyperglycemia in Akita mice (480±33mg/dL). The 20,748 detected annotated protein-coding genes included robust enrichment of S1-segment marker genes. Akita showed 198 (~1%) differentially expressed genes vs. WT (DEGs; adjusted p<0.1) including downregulation of anionic transport, unsaturated fatty acid and carboxylic acid metabolism. Dapa changed only 2 genes in WT but restored 43% of DEGs in Akita, including upregulation of lipid metabolic pathway, carboxylic acid metabolism and organic anion transport. In Akita, sema restored ~10% of DEGs, and Sglt1-KO and dapa were synergistic (restored ~61%) possibly involving additive blood glucose effects (193±15mg/dl). Targeted analysis of transporters and channels (t-test p<0.05) revealed that ~10% of 526 detectable transporters and channels were downregulated by Akita, with ~60% restored by dapa. Dapa, dapa+Sglt1-KO and sema also altered Akita-insensitive genes. Among DEGs in Akita, ~30% were unresponsive to any treatment, indicating potential new targets. In conclusion, SGLT2i restored transcription for multiple metabolic pathways and transporters in SGLT2-positive proximal tubule segments in diabetic mice, with a smaller effect also observed for GLP1R agonism.
2024-11-14 | GSE279174 | GEO
Project description:Inhibitors of SGLT2 (SGLT2i) and diabetes enhance glucose delivery and reabsorption in late proximal tubule S3 segments. However, the molecular consequences remain poorly understood. Here we determined transcriptomic changes in S3 segments of male adult DBA wildtype (WT) and littermate diabetic Akita mice ± Sglt1 knockout (Sglt1-KO) given vehicle or SGLT2i dapagliflozin for 2 weeks, and in Akita mice receiving GLP1R agonist (GLP1RA) semaglutide. RNA sequencing was performed in S3 segments isolated by immunostaining-guided laser-capture-microdissection in deep cortex/outer medulla. Among 19,068 detected annotated genes, 838 genes were differentially expressed by SGLT2i in WT (DEGs; p<0.05) and 1,410 genes in Akita vs. WT. ~34% of SGLT2i-sensitive genes changed in same direction in Akita. Both maneuvers upregulated pathways of cellular proliferation (confirmed by phospho-Ser10 Histone H3 staining) and cellular response to stress, while downregulating pathways of immune/inflammatory response, cytokine production/receptor signaling, and cell adhesion/migration. Both maneuvers also induced unique responses. Unique pathway responses to SGLT2i in WT included increase in DNA dealkylation/demethylation and lysosomal acidification, and reduced valine biosynthesis. Differences in Sglt1-dependency of responses to Akita versus SGLT2i in WT suggested different initiating mechanisms. In Akita mice, inhibition of SGLT2, Sglt1-KO and GLP1R agonism restored 12, 18 and 25% of DEGs, respectively. Akita downregulated whole kidney SGLT1 membrane expression, potentially to limit glucose-induced stress. GLP1RA reduced/restored cellular stress response and proliferation in Akita in S3 segments, associated with enhanced/restored kidney membrane expression of SGLT1. Finally, Akita-sensitive genes unresponsive to any of the 3 maneuvers were identified that may indicate new therapeutic avenues.
2026-06-01 | GSE325466 | GEO
Project description:Transcriptomics of S3 segment in mice: response to type 1 diabetes, SGLT1/2 inhibition, or GLP1 receptor agonism response to type 1 diabetes, SGLT1/2 inhibition or GLP1 receptor agonism
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Project description:Therapeutic PYY/GLP-1 receptor co-agonism in obese-diabetic mice synergistically activates discrete hypothalamic and brainstem neuronal circuitries for weight reduction, increased insulin sensitization, recovery of pancreatic ß-cell function and diabetes remission. GLP1-R agonism (IP118) and PYY-2R agonism (PY115) in combination yield surprising synergistic effects on energy homeostasis in mammals. To better understand the genesis of these effects, RNAseq profiling was performed on key brain regions following an acute dose of IP118+PY115.
2021-03-01 | GSE160802 | GEO
Project description:We sequenced mRNAs from glomeruli and 14 different rat renal tubule segments collected by hand microdissection. Collagenase-digested rat renal tubule segments were collected by hand microdissection. Poly(A)-mRNAs were captured from cell lysate and sequenced using paired-end protocol.
2015-03-31 | E-GEOD-56743 | biostudies-arrayexpress
Project description:We sequenced mRNAs from glomeruli and 14 different rat renal tubule segments collected by hand microdissection.
2015-03-31 | GSE56743 | GEO
Project description: Not available
| S-EPMC6124499 | biostudies-literature
Project description:This a model from the article:
Biophysical characteristics of the pig kidney Na+/glucose cotransporter SGLT2
reveal a common mechanism for SGLT1 and SGLT2.
Mackenzie B, Loo DD, Panayotova-Heiermann M, Wright EM. J Biol Chem
1996 Dec 20;271(51):32678-83 8955098
,
Abstract:
The Na+-dependent, low affinity glucose transporter SGLT2 cloned from pig kidney
is 76% identical (at the amino acid level) to its high affinity homologue SGLT1.
Using two-microelectrode voltage clamp, we have characterized the
presteady-state and steady-state kinetics of SGLT2 expressed in Xenopus oocytes.
The kinetic properties of the steady-state sugar-evoked currents as a function
of external Na+ and alpha-methyl-D-glucopyranoside (alphaMG) concentrations were
consistent with an ordered, simultaneous transport model in which Na+ binds
first. Na+ binding was voltage-dependent and saturated with hyperpolarizing
voltages. Phlorizin was a potent inhibitor of the sugar-evoked currents (KiPz
approximately 10 microM) and blocked an inward Na+ current in the absence of
sugar. SGLT2 exhibited Na+-dependent presteady-state currents with time
constants 3-7 ms. Charge movements were described by Boltzmann relations with
apparent valence approximately 1 and maximal charge transfer approximately 11
nC, and were reduced by the addition of sugar or phlorizin. The differences
between SGLT1 and SGLT2 were that (i) the apparent affinity constant (K0.5) for
alphaMG (approximately 3 mM) was an order of magnitude higher for SGLT2; (ii)
SGLT2 excluded galactose, suggesting discrete sugar binding; (iii) K0.5 for Na+
was lower in SGLT2; and (iv) the Hill coefficient for Na+ was 1 for SGLT2 but 2
for SGLT1. Simulations of the six-state kinetic model previously proposed for
SGLT1 indicated that many of the kinetic properties observed in SGLT2 are
expected by simply reducing the Na+/glucose coupling from 2 to 1.
This model was taken from the CellML repository
and automatically converted to SBML.
The original model was:
Mackenzie B, Loo DD, Panayotova-Heiermann M, Wright EM. () - version=1.0
The original CellML model was created by:
Jonna Terkildsen
j.terkildsen@auckland.ac.nz
The University of Auckland
This model originates from BioModels Database: A Database of Annotated Published Models (http://www.ebi.ac.uk/biomodels/). It is copyright (c) 2005-2011 The BioModels.net Team.
To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication
for more information.
In summary, you are entitled to use this encoded model in absolutely any manner you deem suitable, verbatim, or with modification, alone or embedded it in a larger context, redistribute it, commercially or not, in a restricted way or not..
To cite BioModels Database, please use: Li C, Donizelli M, Rodriguez N, Dharuri H, Endler L, Chelliah V, Li L, He E, Henry A, Stefan MI, Snoep JL, Hucka M, Le Novère N, Laibe C (2010) BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. BMC Syst Biol., 4:92.
2005-01-01 | MODEL1006230076 | BioModels
Project description:The CANVAS program revealed that the SGLT2 inhibitor canagliflozin increases the risk for lower-limb (minor) amputations in type 2 diabetics about a two-fold. On the contrary, the large RCTs with empagliflozin and dapagliflozin did not demonstrate a similar observation. Thus, a question arises whether the increased risk for minor amputations is associated only with canagliflozin or whether it is a class effect of SGLT2 inhibitors. Vascular disorders including defective angiogenesis are among the leading causes of lower-limb amputations. Therefore, here we examined the effects of empagliflozin, dapagliflozin, and canagliflozin on angiogenesis using zebrafish embryos and HUVECs.
2022-12-31 | GSE191046 | GEO
Project description:SGLT2 inhibitors and zebrafish
| PRJNA789531 | ENA