Authors
Petter Bjornstad, Ye Ji Choi, Phoom Narongkiatikhun, Anil Karihaloo, Pottumarthi V Prasad, Lu-Ping Li, Kalie L Tommerdahl, Maninderpal Sethi, Shivani Ramesh, Carissa Birznieks, Antoine Clarke, Yesmino Elia, Jacqueline Curtis, Cheril Clarson, Dylan Weissenkampen, Matteo D'Antonio, Jairo Arturo Pinzon Cortes, Hailey Hampson, Long Yuan, Sarah A van Eeghen, Jenny E Kanter, Karin E Bornfeldt, Tomas Vaisar, Patricia Ladd, Hiddo J L Heerspink, Ian H de Boer, Jesse A Goodrich, Kelly Street, Katherine R Tuttle, Kelly R Bergmann, Cathy Smith, Jeffrey B Hodgin, Jennifer A Schaub, Viji Nair, Rajasree Menon, Abhijit S Naik, Phillip J McCown, Fadhl AlAkwaa, Sean Eddy, Edgar Otto, Nan Hee Kim, Robert G Nelson, Victor G Puelles, Daniël H van Raalte, David Z I Cherney, Laura Pyle, Farid H Mahmud, Matthias Kretzler
Published in
Science translational medicine. Volume 18. Issue 859. Pages eaee1005. Jul 22, 2026. Epub Jul 22, 2026.
Abstract
Sodium-glucose cotransporter-2 (SGLT2) inhibitors slow diabetic kidney disease progression, but their intrarenal mechanisms remain incompletely understood, particularly in type 1 diabetes (T1D), where kidney protection has not been definitively established. ATTEMPT (NCT04333823) was a placebo-controlled trial in which 98 youth (ages 12 to 21) with T1D and hyperfiltration were randomized 1:1 to dapagliflozin (5 milligrams) or placebo for 16 weeks. Participants underwent sequential kidney biopsies, multiparametric kidney MRI, and plasma and urine proteomics. The sequential research kidney biopsies were performed on adults 18 years or older at one of three sites (baseline n = 16, follow-up n = 11). Single-cell RNA sequencing of 214,415 cells across 27 biopsies revealed coordinated transcriptional shifts across nephron, vascular, and immune compartments. In the proximal tubule, the primary site of SGLT2 expression, dapagliflozin down-regulated glycolysis, gluconeogenesis, and oxidative stress markers. Endothelial cells showed reduced profibrotic and inflammatory gene expression with increased protective factors. Podocytes demonstrated enhanced cytoskeletal reinforcement and suppressed interferon signaling. These molecular changes paralleled clinical improvements, including attenuation of hyperfiltration, improved glycemic control, and normalization of medullary oxygenation. Trajectory analyses revealed dapagliflozin shifted tubular cells from injury-prone toward healthier phenotypes. Cross-cohort comparison against healthy controls showed that more than 55% of dapagliflozin-responsive genes shifted toward healthy control expression patterns. Urine proteomics mirrored tissue changes with decreased injury markers and increased protective proteins. These convergent molecular mechanisms, metabolic reprogramming, dampened inflammation, and normalized oxygen handling provide hypothesis-generating mechanistic insights into potential kidney-protective mechanisms of SGLT2 inhibitor therapy in youth with T1D.
PMID:
42485434
Bibliographic data and abstract were imported from PubMed on 23 Jul 2026.
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