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Transcriptomics of SGLT2-positive early proximal tubule segments in mice: response to type 1 diabetes, SGLT1/2 inhibition, or GLP1 receptor agonism
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 wild-type (WT) and littermate diabetic Akita mice ± Sglt1 knockout (Sglt1-KO) were given vehicle or SGLT2i dapagliflozin (dapa; 10 mg/kg diet) for 2 wk, and other Akita mice received GLP1R agonist semaglutide [sema; 3 nmol/(kg body wt·day), sc]. Dapa (254 ± 11 mg/dL) and Sglt1-KO (367 ± 11 mg/dL) but not sema (407 ± 44 mg/dL) significantly reduced hyperglycemia in Akita mice (480 ± 33 mg/dL). The 20,748 detected annotated protein-coding genes included robust enrichment of S1-segment marker genes. Akita showed 198 (~1%) differentially expressed genes versus WT (DEGs; adjusted P ≤ 0.1), including downregulation of anionic transport, unsaturated fatty acid, and carboxylic acid metaboli sm. Dapa changed only two genes in WT but restored 43% of DEGs in Akita, including upregulation of the 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 ± 15 mg/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. © 2025 American Physiological Society. All rights reserved.
Authors : Kim Y.C.; Das V.; Kanoo S.; Yao H.; Stanford S.M.; Bottini N.; Karihaloo A.; Vallon V.
Source : American Physiological Society
Article Information
| Year | 2025 |
| Type | Article |
| DOI | 10.1152/ajprenal.00231.2024 |
| ISSN | 1931857X |
| Volume | 328 |
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