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Abstract: FR-OR40

Transcriptomics of SGLT2-Positive Proximal Tubule S1 Segments in Mice: Response to Diabetes, SGLT1/2 Inhibition, or GLP1 Receptor Agonist

Session Information

Category: Diabetic Kidney Disease

  • 701 Diabetic Kidney Disease: Basic

Authors

  • Kim, Young Chul, University of California San Diego, La Jolla, California, United States
  • Das, Vivek, Novo Nordisk Research Center, Seattle, Washington, United States
  • Kanoo, Sadhana, VA San Diego Healthcare System, San Diego, California, United States
  • Stanford, Stephanie, University of California San Diego, La Jolla, California, United States
  • Bottini, Nunzio, University of California San Diego, La Jolla, California, United States
  • Karihaloo, Anil K., Novo Nordisk Research Center, Seattle, Washington, United States
  • Vallon, Volker, University of California San Diego, La Jolla, California, United States
Background

SGLT2 inhibitors (SGLT2i) and GLP1 receptor (GLP1R) agonists have kidney protective effects. However, their molecular effects on SGLT2-expressing early proximal tubule S1 segments, which have negligible SGLT1 expression, have not been fully understood.

Methods

Fourteen week-old male wildtype (DBA) and diabetic (DBA-Akita) mice ± systemic Sglt1 knockout (ko) were given vehicle or SGLT2i dapagliflozin (Dapa; 10mg/kg diet) for 2 weeks, while other DBA-Akita received GLP1R agonist semaglutide (Sema; 3nmol/[kg body weight*day], s.c.). RNA sequencing was performed in SGLT2-positive proximal tubule segments isolated by immunostaining-guided laser capture microdissection (IS-LCM) using a Sglt2 ko-validated antibody (n=6 mice/group).

Results

Blood glucose in DBA-Akita was significantly reduced by Dapa (254±11mg/dL) and Sglt1 ko (367±11mg/dL) but not by Sema (407±44mg/dL) vs. vehicle (480±33mg/dL). A total of 20,748 annotated protein-coding genes was detected by RNA sequencing, and robust enrichment of S1 segment genes was confirmed by ranking marker genes based on the number of transcripts. DBA-Akita showed 116 differentially expressed genes vs. DBA (DEGs; adjusted p<0.1, log2FC +/-0.6) suggesting downregulation of metabolic pathways like unsaturated fatty acid and carboxylic acid metabolism. Dapa restored 40/116 genes and increased genes in lipid metabolic pathway, carboxylic acid metabolism and organic anion transport. Meanwhile, Dapa changed only 2 genes in DBA. Moreover, Sema and Sglt1 ko restored only 11 and 0 of the DEGs in DBA-Akita. Sglt1 ko enhanced the Dapa effect in DBA-Akita (207 DEGs and 64 restored genes) possibly due to additive effects on blood glucose (193±15mg/dl).

Conclusion

Transcriptomic profiling of SGLT2-positive S1 segments was established by IS-LCM. Despite SGLT2 expression in these segments, SGLT2i had little effect on transcriptomics in non-diabetic conditions. In diabetic mice, however, it restored transcription for multiple metabolic pathways, while targeting GLP1R or SGLT1 showed little effect. The approach warrants further studies in SGLT1-expressing S3 segments, which compensate during SGLT2i, and in glomeruli.

Funding

  • NIDDK Support – Novo Nordisk