1113-OR: ADA Presidents' Select Abstract: Single-Cell Transcriptomic Profiling Identifies GLP-1RA Associated Pathways in Early Kidney Disease

Introduction and Objective: In REMODEL, semaglutide improved endothelial cell (EC) health in adults with type 2 diabetes (T2D) and chronic kidney disease (KD), but intrarenal mechanisms of glucagon-like peptide-1 receptor agonists (GLP-1RA) are unclear. We identified intrarenal genes and pathways responsive to GLP-1RA use in KD. Methods: scRNA-seq analysis was done in kidney biopsy tissue from 11 participants with KD (UACR ≥30 mg/g or eGFR <90 mL/min/1.73m2; Fig A). Genes expressed in ≥5% of cells in at least 1 major cell type were included, and ~118k cells remained after quality control (Fig B). NEBULA was used for cell type specific differential gene expression (DEG) between GLP-1RA users/non-users, followed by gene set enrichment analysis. Results: Figs D-K summarize findings in immune lymphoid, cortical thick ascending limb 2 (C-TAL-2), EC/vascular smooth muscle cells (VSMC), and immune myeloid cells, which had the highest numbers of DEGs (Fig C). Angiogenesis was enriched in immune cells, whereas hypoxia and TNFα-NFκB signaling were suppressed in immune myeloid cells. Glycolysis was enriched in EC/VSMC, whereas hypoxia and multiple metabolic pathways, including fatty acid metabolism, glycolysis, and oxidative phosphorylation, were suppressed in immune and C-TAL-2 cells. Conclusion: GLP-1RA use in early KD is associated with distinct vascular, immune, and tubular pathway signatures, extending prior observations of EC effects to the intrarenal cellular level. Disclosure Y. Choi: None. H. Hampson: None. J.D. Weissenkampen: None. J. Kanter: None. T. Vaisar: None. K. Sulek: Employee; Current; Novo Nordisk A/S. K. Bornfeldt: Advisory Panel; Current; ESPERION Therapeutics, Inc. J.A. Schaub: Consultant; Ended; Klick. D. van Raalte: Consultant; Current; AstraZeneca. Research Support; Current; AstraZeneca. Consultant; Current; Boehringer Ingelheim International GmbH. Research Support; Current; Boehringer Ingelheim International GmbH. Consultant; Current; Eli Lilly and Company. Research Support; Current; Eli Lilly and Company. Consultant; Current; Merck & Co., Inc. Research Support; Current; Merck & Co., Inc. Consultant; Current; Novo Nordisk. Research Support; Current; Novo Nordisk. K.J. Nadeau: None. S. Eddy: Research Support; Current; AstraZeneca, Eli Lilly and Company, Genentech, Inc., Sanofi, Novo Nordisk A/S, Travere Therapeutics. Other - Royalties administered through University of Michigan; Current; AstraZeneca. Research Support; Current; Certa Therapeutics, Vera Therapeutics, Dimerix. V. Nair: None. P. McCown: None. A.S. Naik: None. M.O. Alaba: None. F. Alakwaa: None. N. Nguyen: None. C. Smith: None. J.B. Hodgin: None. R. Nelson: None. K. Tuttle: Consultant; Ended; Alnylam Pharmaceuticals, Inc. Consultant; Current; AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, GlaxoSmithKline plc., Novo Nordisk, Lilly, ProKidney. Consultant; Ended; Roche Diabetes Care. Research Support; Ended; Travere. P.E. Ladd: None. E. Zeitler: Consultant; Current; Novo Nordisk. A. Karihaloo: None. M. Kretzler: Research Support; Current; AstraZeneca, Boehringer Ingelheim International GmbH, Bayer AG, Dimerix, Eli Lilly and Company, F. Hoffmann-La Roche Ltd., European Union, JDRF, National Institutes of Health, Novo Nordisk, Sanofi, vera therapeutics, Regeneron Pharmaceuticals Inc., Travere. P. Bjornstad: Consultant; Current; Bayer AG, Boehringer Ingelheim International GmbH, Lilly, Novo Nordisk. Funding Children's Hospital of Colorado