SGLT2 inhibitors mitigate kidney tubular metabolic and mTORC1 perturbations in youth-onset type 2 diabetes
Jennifer A. Schaub, Fadhl M. AlAkwaa, Phillip J. McCown, Abhijit S. Naik, Viji Nair, Sean Eddy, Rajasree Menon, Edgar A. Otto, Dawit Demeke, John Hartman, Damian Fermin, Christopher L. O’Connor, Lalita Subramanian, Markus Bitzer, Roger Harned, Patricia Ladd, Laura Pyle, Subramaniam Pennathur, Ken Inoki, Jeffrey B. Hodgin, Frank C. Brosius III, Robert G. Nelson, Matthias Kretzler, Petter Bjornstad
Jennifer A. Schaub, Fadhl M. AlAkwaa, Phillip J. McCown, Abhijit S. Naik, Viji Nair, Sean Eddy, Rajasree Menon, Edgar A. Otto, Dawit Demeke, John Hartman, Damian Fermin, Christopher L. O’Connor, Lalita Subramanian, Markus Bitzer, Roger Harned, Patricia Ladd, Laura Pyle, Subramaniam Pennathur, Ken Inoki, Jeffrey B. Hodgin, Frank C. Brosius III, Robert G. Nelson, Matthias Kretzler, Petter Bjornstad
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Research Article Metabolism Nephrology

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

Abstract

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.

Authors

Jennifer A. Schaub, Fadhl M. AlAkwaa, Phillip J. McCown, Abhijit S. Naik, Viji Nair, Sean Eddy, Rajasree Menon, Edgar A. Otto, Dawit Demeke, John Hartman, Damian Fermin, Christopher L. O’Connor, Lalita Subramanian, Markus Bitzer, Roger Harned, Patricia Ladd, Laura Pyle, Subramaniam Pennathur, Ken Inoki, Jeffrey B. Hodgin, Frank C. Brosius III, Robert G. Nelson, Matthias Kretzler, Petter Bjornstad

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Figure 3

SGLT2 inhibition altered transcript expression in the majority of tubular cell segments.

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SGLT2 inhibition altered transcript expression in the majority of tubula...
(A) Plot of the number of transcripts reversed, suppressed, or enhanced with SGLT2i shows that the majority of transcripts altered with SGLT2i were in distal nephron segments. The fold changes (log2FC) were calculated between 2 comparisons: T2Di(–) versus HCs and T2Di(+) versus T2Di(–). Transcripts were required to pass FDR-adjusted P values of less than 0.05 in T2Di(–) versus HCs and in T2Di(+) versus T2Di(–) to be considered reversed. (B) Upset plots indicate most transcripts suppressed with SGLT2i were in DTL. DTL and IC shared the greatest number of transcripts. (C) Most unique transcripts enhanced with SGLT2i were in PC, TAL, and DTL. PC and TAL had the greatest number of overlapping transcripts (n = 135). Using the Reactome database and Fisher’s exact test, (D) central metabolic pathways in PT, DTL, and IC were suppressed and (E) all central metabolic processes were enhanced in TAL. Metallothioneins were enhanced across all segments, except DTL.