Metabolic surgery mitigates early kidney injury in obese youth with diabetes by suppressing mTORC1/JAK/STAT signaling
Abhijit S. Naik, et al.
Abhijit S. Naik, et al.
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Clinical Research and Public Health Metabolism Nephrology

Metabolic surgery mitigates early kidney injury in obese youth with diabetes by suppressing mTORC1/JAK/STAT signaling

Abstract

BACKGROUND Youth with type 2 diabetes (T2D) and severe obesity face high risk of diabetic kidney disease, which metabolic bariatric surgery (MBS) can mitigate. This study explores structural and molecular changes in kidneys after vertical sleeve gastrectomy (VSG), a form of MBS.METHODS We performed paired analyses, including metabolic profiling, kidney volume assessment, histological evaluation, and single-cell RNA sequencing (scRNA-seq), on kidney biopsies from 5 youth with T2D and obesity pre- and 12 months post-VSG in the IMPROVE-T2D (Impact of Metabolic surgery on Pancreatic, Renal and cardiOVascular hEalth in youth with T2D) cohort. Circulating proteomics with kidney transcriptomics were linked using data from an independent cohort of youth with obesity, with or without T2D, undergoing MBS in Teen-Longitudinal Assessment of Bariatric Surgery (Teen-LABS, n = 64).RESULTS After VSG, participants lost weight and had improvements in insulin sensitivity and metabolic parameters. Kidney changes included reduced renal hyperfiltration, total kidney volume, mesangial matrix area, and microalbuminuria. scRNA-seq in proximal tubule (PT) and thick ascending limb cells indicated repression of glycolysis, gluconeogenesis, and tricarboxylic acid (TCA) cycle genes, with upregulation of AMP-activated protein kinase (AMPK) and forkhead box O3 (FOXO3). Decreased metabolic signaling aligned with reduced ribosomal phosphorylated S6K (pS6K), suggesting attenuated mTORC1 activity. Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway activation in PT was diminished, correlating with lower circulating ligands from Teen-LABS proteomic data.CONCLUSION MBS/VSG prompts kidney molecular adaptations, providing potential targets for nonsurgical interventions against obesity- and diabetes-associated kidney disease.FUNDING University of Washington with the American Diabetes Association, University of Michigan with Chan Zuckerberg Initiative, and Breakthrough T1D.

Authors

Abhijit S. Naik, Fadhl M. Alakwaa, Viji Nair, Phillip J. McCown, Jennifer A. Schaub, Edgar A. Otto, Rajasree Menon, Francesca Annese, Ye Ji Choi, Hailey E. Hampson, Thomas H. Inge, John Hartman, Sean Eddy, Cathy Smith, Jeffrey B. Hodgin, Ken Inoki, Swayam Prakash Srivastava, Kareem Al-Fagih, Shota Yoshida, Jesse A. Goodrich, Melanie G. Cree, Phoom Narongkiatikhun, Long Yuan, Kalie L. Tommerdahl, Pottumarthi Prasad, Daniël H. van Raalte, Megan M. Kelsey, Justin R. Ryder, Tyler J. Dobbs, Patricia Ladd, Subramaniam Pennathur, Robert G. Nelson, Yusuke Okabayashi, Victor G. Puelles, Jenna Ferrence-Salo, Jeffrey A. Beamish, Frank C. Brosius, Kristen J. Nadeau, Laura Pyle, Matthias Kretzler, Petter Bjornstad

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Figure 8

Pathway enrichment analysis of pseudobulk differential gene expression in proximal tubular epithelial cells.

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Pathway enrichment analysis of pseudobulk differential gene expression i...
(A) The data reveal significant enrichment of the JAK/STAT signaling pathway, EGFR-mediated signaling, and p53 signaling, all of which were markedly reduced following VSG. *P <.05, **P <.01, ***P <.001, ****P <.0001. Wald’s test was used to determine P values. (B) JAK/STAT activation was assessed at the individual patient level using the single-sample gene set enrichment analysis (ssGSEA) method. A consistent reduction in JAK/STAT activation was observed across all patients post-VSG. (C) Expression levels of IFNAR1 and IFNGR2 (type 1 and type 2 interferon receptors, respectively), which signal through the JAK/STAT pathway, were significantly reduced post-VSG. This reduction was accompanied by decreased circulating levels of a type 1 interferon (IFNA7) but not type 2 interferons. Additionally, an increased expression of prolactin receptor (PRLR), a paralog of GH1, was noted. This upregulation is hypothesized to result from reduced circulating prolactin (PRL), triggering a compensatory negative feedback loop. (D) Average change in expression of 3 genes, apolipoprotein L6 (APOL6), proteasome 20S subunit β9 (PSMB9), and transmembrane protein 140 (TMEM140), which are among the genes used to calculate JAK/STAT activation score.