SGLT2 inhibitors mitigate kidney tubular metabolic and mTORC1 perturbations in youth

TY - JOUR

T1 - SGLT2 inhibitors mitigate kidney tubular metabolic and mTORC1 perturbations in youth-onset type 2 diabetes

AU - Schaub, Jennifer A.

AU - AlAkwaa, Fadhl M.

AU - McCown, Phillip J.

AU - Naik, Abhijit S.

AU - Nair, Viji

AU - Eddy, Sean

AU - Menon, Rajasree

AU - Otto, Edgar A.

AU - Demeke, Dawit

AU - Hartman, John

AU - Fermin, Damian

AU - O’Connor, Christopher L.

AU - Subramanian, Lalita

AU - Bitzer, Markus

AU - Harned, Roger

AU - Ladd, Patricia

AU - Pyle, Laura

AU - Pennathur, Subramaniam

AU - Inoki, Ken

AU - Hodgin, Jeffrey B.

AU - Brosius, Frank C.

AU - Nelson, Robert G.

AU - Kretzler, Matthias

AU - Bjornstad, Petter

N1 - Funding Information: We like to thank Yingbao Yang for his expert technical support. This work was supported in part by the University of Michigan O’Brien Kidney Translational Core Center grant (P30 DK081943) and a grant from the JDRF Center for Excellence (5-COE-2019-861-S-B) to MK and SP. The Renal HEIR, IMPROVE-T2D, and CROCODILE studies were supported by the NIDDK (K23 DK116720, R01 DK132399, UC2 DK114886, and P30 DK116073), JDRF (2-SRA-2019-845-S-B, 3-SRA-2022-1097-M-B), the 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. PB receives salary and research support from the NIDDK (R01 DK129211, R01 DK132399, RO1 HL165433, R21 DK129720, K23 DK116720, and UC2 DK114886), JDRF (3-SRA-2022-1097-M-B, 3-SRA-2022-1243-M-B, and 3-SRA-2022-1230-M-B), the Boettch-er Foundation, the American Heart Association (20IPA35260142), the Ludeman Family Center for Women’s Health Research at the University of Colorado, the Department of Pediatrics, Section of Endocrinology, and the Barbara Davis Center for Diabetes at University of Colorado School of Medicine. JAS receives salary and research support from the NIDDK (K08 DK124449) and the Michigan Diabetes Research Center. ASN receives salary and research support from the NIDDK (K23 DK125529). MB was supported by R01 DK100449. KI receives salary and research support from the NIDDK and the National Institute of General Medical Sciences (NIGMS) (R01 DK124709, R01 GM145631). Publisher Copyright: Copyright: © 2023, Schaub et al.

PY - 2023/3/1

Y1 - 2023/3/1

N2 - The molecular mechanisms of sodium-glucose cotransporter-2 (SGLT2) inhibitors (SGLT2i) remain incompletely understood. Single-cell RNA sequencing and morphometric data were collected from research kidney biopsies donated by young persons with type 2 diabetes (T2D), aged 12 to 21 years, and healthy controls (HCs). Participants with T2D were obese and had higher estimated glomerular filtration rates and mesangial and glomerular volumes than HCs. Ten T2D participants had been prescribed SGLT2i (T2Di[+]) and 6 not (T2Di[–]). Transcriptional profiles showed SGLT2 expression exclusively in the proximal tubular (PT) cluster with highest expression in T2Di(–) patients. However, transcriptional alterations with SGLT2i treatment were seen across nephron segments, particularly in the distal nephron. SGLT2i treatment was associated with suppression of transcripts in the glycolysis, gluconeogenesis, and tricarboxylic acid cycle pathways in PT, but had the opposite effect in thick ascending limb. Transcripts in the energy-sensitive mTORC1-signaling pathway returned toward HC levels in all tubular segments in T2Di(+), consistent with a diabetes mouse model treated with SGLT2i. Decreased levels of phosphorylated S6 protein in proximal and distal tubules in T2Di(+) patients confirmed changes in mTORC1 pathway activity. We propose that SGLT2i treatment benefits the kidneys by mitigating diabetes-induced metabolic perturbations via suppression of mTORC1 signaling in kidney tubules.

AB - The molecular mechanisms of sodium-glucose cotransporter-2 (SGLT2) inhibitors (SGLT2i) remain incompletely understood. Single-cell RNA sequencing and morphometric data were collected from research kidney biopsies donated by young persons with type 2 diabetes (T2D), aged 12 to 21 years, and healthy controls (HCs). Participants with T2D were obese and had higher estimated glomerular filtration rates and mesangial and glomerular volumes than HCs. Ten T2D participants had been prescribed SGLT2i (T2Di[+]) and 6 not (T2Di[–]). Transcriptional profiles showed SGLT2 expression exclusively in the proximal tubular (PT) cluster with highest expression in T2Di(–) patients. However, transcriptional alterations with SGLT2i treatment were seen across nephron segments, particularly in the distal nephron. SGLT2i treatment was associated with suppression of transcripts in the glycolysis, gluconeogenesis, and tricarboxylic acid cycle pathways in PT, but had the opposite effect in thick ascending limb. Transcripts in the energy-sensitive mTORC1-signaling pathway returned toward HC levels in all tubular segments in T2Di(+), consistent with a diabetes mouse model treated with SGLT2i. Decreased levels of phosphorylated S6 protein in proximal and distal tubules in T2Di(+) patients confirmed changes in mTORC1 pathway activity. We propose that SGLT2i treatment benefits the kidneys by mitigating diabetes-induced metabolic perturbations via suppression of mTORC1 signaling in kidney tubules.

UR - http://www.scopus.com/inward/record.url?scp=85149154030&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85149154030&partnerID=8YFLogxK

U2 - 10.1172/JCI164486

DO - 10.1172/JCI164486

M3 - Article

C2 - 36637914

AN - SCOPUS:85149154030

SN - 0021-9738

VL - 133

JO - Journal of Clinical Investigation

JF - Journal of Clinical Investigation

IS - 5

M1 - :e164486

ER -