Omics · study · 2026
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
Listed in NCBI GEO
Inhibitors of SGLT2 (SGLT2i) and diabetes enhance glucose delivery and reabsorption in late proximal tubule S3 segments.
Description
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.
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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.
Links
Get the data
- GEO FTP directory ftp.ncbi.nlm.nih.gov/geo/series/GSE325nnn/GSE325466 ↗
download · from NCBI GEO
Where it is published
- GEO accession page ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE325466 ↗
landing page · from NCBI GEO
Documentation and papers
- PRJNA1440221 ncbi.nlm.nih.gov/bioproject/PRJNA1440221 ↗
project · from NCBI GEO
- PubMed 42213650 pubmed.ncbi.nlm.nih.gov/42213650 ↗
publication · from NCBI GEO
Topics
- Stated by source
- Expression profiling by high throughput sequencing · Mus musculus
- From keywords
- Life Sciences
- Inferred from text
- RNA sequencing 75% · Sequencing 75%
Provenance · 1 source records, 9 field assertions
| Source | Key | Last seen | Raw |
|---|---|---|---|
| NCBI GEO | GSE325466 | 15 d ago | JSON v1 |
| Field | Assertion | Extractor | Evidence |
|---|---|---|---|
| access_level | source · NCBI GEO | connector:ncbi_geo@1.0.0 | |
| concepts[field].local:field:life-sciences | mapping · NCBI GEO | connector:ncbi_geo@1.0.0 | |
| concepts[method].geo_series_type:expression-profiling-by-high-throughput-sequencing | source · NCBI GEO | connector:ncbi_geo@1.0.0 | /gdstype |
| concepts[modality].local:modality:rna-seq | enrichment · NCBI GEO | keyword-concept-rules@1.0.0 | title+description (75%) |
| concepts[modality].local:modality:sequencing | enrichment · NCBI GEO | keyword-concept-rules@1.0.0 | title+description (75%) |
| concepts[organism].NCBITaxon:10090 | source · NCBI GEO | connector:ncbi_geo@1.0.0 | /taxon |
| description | source · NCBI GEO | connector:ncbi_geo@1.0.0 | /summary |
| publication_date | source · NCBI GEO | connector:ncbi_geo@1.0.0 | |
| title | source · NCBI GEO | connector:ncbi_geo@1.0.0 | /title |