SGLT2 inhibition mitigates perturbations in nephron segment-specific metabolic transcripts and mTOR pathway activity in kidneys of young persons with type 2 diabetes

The molecular mechanisms of SGLT2 inhibitors (SGLT2i) remain incompletely understood. Single-cell RNA sequencing and morphometrics data were collected from research kidney biopsies donated by participants with youth onset type 2 diabetes (T2D), aged 12-21 years of age, and healthy controls (HC) to study the effects of SGLT2i on kidney transcriptomics. Participants with T2D were more obese, had higher glomerular filtration rate, mesangial and glomerular volumes than HC. There were no clinically significant differences between participants prescribed SGLT2i (T2Di(+), n=10) and other T2D (T2Di(-), n=6). Transcriptional profiles showed SGLT2 expression exclusively in the proximal tubular (PT) cluster. Transcriptional alterations in T2Di(+) compared to T2Di(-) were seen across most nephron segments, most prominently in the distal nephron. SGLT2i treatment was associated with suppression of genes in the glycolysis, gluconeogenesis, tricarboxylic acid cycle pathways in PT, but enhanced expression in thick ascending limb. The energy sensitive mTOR signaling pathway transcripts were suppressed towards HC level in all nephron segments in T2Di(+). These transcriptional changes were confirmed in a diabetes mouse model treated with SGLT2i. Therefore, the beneficial effects of SGLT2i treatment to the kidneys might be from mitigating diabetes-induced metabolic perturbations via suppression of mTORC1 signaling across nephron segments, including those not expressing SGLT2.