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.

Dr. M. Kretzler reports grants from NIH/NIDDK in support of this manuscript. Grants and contracts outside the submitted work through the University of Michigan with NIH, Chan Zuckerberg Initiative, JDRF, AstraZeneca, NovoNordisk, Eli Lilly, Gilead, Goldfinch Bio, Janssen, Boehringer-Ingelheim, Moderna, European Union Innovative Medicine Initiative, Certa, Chinook, amfAR, Angion, RenalytixAI, Travere, Regeneron, IONIS, consulting fees through the University of Michigan from Astellas, Poxel, Janssen and UCB. In addition, Dr. Kretzler has a patent PCT/EP2014/073413, Biomarkers and methods for progression prediction for chronic kidney disease, licensed.

This work was supported in part by the University of Michigan OBrien Kidney Translational Core Center grant (P30 DK081943) to M.K. The Renal-HEIR/IMPROVE-T2D and CROCODILE studies were supported by NIDDK (K23 DK116720, R01 DK132399, UC2 DK114886, P30 DK116073), JDRF (2-SRA-2019-845-S-B, 3-SRA-2022-1097-M-B), Boettcher Foundation and in part by the Intramural Research Program at NIDDK and the Centers for Disease Control and Prevention (CKD Initiative) under inter-Agency Agreement #21FED2100157DPG. P.B. receives salary and research support from NIDDK (R01 DK129211, R01 DK132399, R21 DK129720, K23 DK116720, UC2 DK114886), JDRF (3-SRA-2022-1097-M-B, 3-SRA-2022-1243-M-B, 3-SRA-2022-1230-M-B), Boettcher Foundation, American Heart Association (20IPA35260142), Ludeman Family Center for Womens Health Research at the University of Colorado, the Department of Pediatrics, Section of Endocrinology and Barbara Davis Center for Diabetes at University of Colorado School of Medicine. J.A.S receives salary and research support from NIDDK (K08 DK124449). A.S.N. receives salary and research support from NIDDK (K23 DK125529). MB was supported by R01 DK100449.

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