Semaglutide and Dapagliflozin Restore Gene Expression in S3 Kidney Segments of Type 1 Diabetic Mice

The S3 segment of the proximal tubule is crucial for glucose reabsorption, a process significantly altered in Type 1 diabetes (T1D). While SGLT2 inhibitors (SGLT2i) and GLP1 receptor agonists (GLP1RA) show kidney benefits, the precise molecular changes within the S3 segment in response to T1D and these therapies remain poorly understood. Understanding these transcriptomic shifts could reveal novel mechanisms for protecting the kidney from diabetic nephropathy and guide more targeted interventions.

Researchers investigated transcriptomic changes in S3 segments of male adult DBA wildtype (WT) and littermate diabetic Akita mice, some with Sglt1-KO. Mice received either vehicle, the SGLT2i dapagliflozin for 2 weeks, or the GLP1RA semaglutide. RNA sequencing was performed on S3 segments precisely isolated by immunostaining-guided laser-capture-microdissection from the deep cortex/outer medulla. Primary endpoints included identification of differentially expressed genes (DEGs) and pathway analysis.

Among 19,068 detected genes, 838 were differentially expressed (DEGs; p<0.05) by SGLT2i in WT mice, and 1,410 DEGs were found in Akita vs. WT. Approximately 34% of SGLT2i-sensitive genes changed in the same direction in Akita mice. Both SGLT2i and GLP1RA interventions 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. Unique SGLT2i responses in WT included increased DNA dealkylation/demethylation and lysosomal acidification, and reduced valine biosynthesis. In Akita mice, SGLT2i, Sglt1-KO, and GLP1RA restored 12%, 18%, and 25% of DEGs, respectively.

GLP1RA semaglutide restored 25% of differentially expressed genes (DEGs) in Akita mice S3 segments, while SGLT2i dapagliflozin restored 12%, and Sglt1-KO restored 18%. Combined SGLT2i/Sglt1-KO was not synergistic. Akita mice downregulated whole kidney SGLT1 membrane expression, and GLP1RA reduced/restored cellular stress and proliferation, associated with enhanced/restored kidney membrane SGLT1 expression.