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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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE325466 | GEO | 2026/06/01

REPOSITORIES: GEO

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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.

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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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