Nephron Segment Specific Response to SGLT2 Inhibitors in Young Persons With Type 2 Diabetes

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Background: Youth-onset type 2 diabetes (T2D) carries a higher risk of diabetic kidney disease (DKD) than type 1 and adult-onset type 2 diabetes of similar duration, with few treatment options. SGLT2 inhibitors (SGLT2i) are protective against DKD, but the mechanisms of nephroprotection are incompletely understood. Methods: Single-cell RNA sequencing (scRNAseq) data and morphometrics were obtained from protocol kidney biopsies in healthy controls (HC, n=6) and participants ranging from 12-21 years with T2D (n=16), either treated with SGLT2i (T2Di+, n=6) or not (T2Di-, n=10). Transcripts elevated in T2D vs. HC but reduced in T2Di vs. T2D were considered “suppressed”, similarly transcripts depressed in T2Di- but elevated in T2Di+ were termed “enhanced”. mTOR activity scores were calculated based on expression of 39 reactome pathway genes. Results: T2D participants were more obese and had higher measured GFR than HC. Morphometric evaluation showed higher mesangial and glomerular volumes in T2D vs. HC. scRNAseq profiles of 40,353 kidney cells formed 18 cell clusters representing all major cell types in the nephron. Despite SGLT2 expression exclusively in proximal tubules (PT), transcripts in the distal nephron were most altered with SGLT2i. In PT, transcripts in central carbon metabolism, including glycolysis, gluconeogenesis, TCA cycle and beta oxidation were suppressed with SGLT2i. In contrast, these pathways in thick ascending limb (TAL) were enhanced with the inhibitor (Fig). Notably, mTOR pathway activity score in T2Di+ reverted towards the level seen in HC than T2Di-. Conclusions: The transcriptional profiles of many metabolic pathways were favorably altered with SGLT2i in a nephron segment-specific manner in young persons with T2D. mTOR may be an important mediator of SGLT2i treatment effects in the kidney. Funding: NIDDK Support

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