Medications Activating Tubular Fatty Acid Oxidation Enhance the Protective Effects of Roux-en-Y Gastric Bypass Surgery in a Rat Model of Early Diabetic Kidney Disease

William P. Martin, Yeong H. D. Chuah, Mahmoud Abdelaal, Anders Pedersen, Daniel Malmodin, Sanna Abrahamsson, Michaela Hutter, Catherine Godson, Eoin P. Brennan, Lars Fändriks, Carel W. le Roux, Neil G. Docherty

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Abstract

Roux-en-Y gastric bypass surgery (RYGB) improves biochemical and histological parameters of diabetic kidney disease (DKD). Targeted adjunct medical therapy may enhance renoprotection following RYGB. The effects of RYGB and RYGB plus fenofibrate, metformin, ramipril, and rosuvastatin (RYGB-FMRR) on metabolic control and histological and ultrastructural indices of glomerular and proximal tubular injury were compared in the Zucker Diabetic Sprague Dawley (ZDSD) rat model of DKD. Renal cortical transcriptomic (RNA-sequencing) and urinary metabolomic ( H-NMR spectroscopy) responses were profiled and integrated. Transcripts were assigned to kidney cell types through deconvolution in kidney single-nucleus RNA-sequencing and microdissected tubular epithelial cell proteomics datasets. Medication-specific transcriptomic responses following RYGB-FMRR were explored using a network pharmacology approach. Omic correlates of improvements in structural and ultrastructural indices of renal injury were defined using a molecular morphometric approach. RYGB-FMRR was superior to RYGB alone with respect to metabolic control, albuminuria, and histological and ultrastructural indices of glomerular injury. RYGB-FMRR reversed DKD-associated changes in mitochondrial morphology in the proximal tubule to a greater extent than RYGB. Attenuation of transcriptomic pathway level activation of pro-fibrotic responses was greater after RYGB-FMRR than RYGB. Fenofibrate was found to be the principal medication effector of gene expression changes following RYGB-FMRR, which led to the transcriptional induction of PPARα-regulated genes that are predominantly expressed in the proximal tubule and which regulate peroxisomal and mitochondrial fatty acid oxidation (FAO). After omics integration, expression of these FAO transcripts positively correlated with urinary levels of PPARα-regulated nicotinamide metabolites and negatively correlated with urinary tricarboxylic acid (TCA) cycle intermediates. Changes in FAO transcripts and nicotinamide and TCA cycle metabolites following RYGB-FMRR correlated strongly with improvements in glomerular and proximal tubular injury. Integrative multi-omic analyses point to PPARα-stimulated FAO in the proximal tubule as a dominant effector of treatment response to combined surgical and medical therapy in experimental DKD. Synergism between RYGB and pharmacological stimulation of FAO represents a promising combinatorial approach to the treatment of DKD in the setting of obesity. [Abstract copyright: Copyright © 2022 Martin, Chuah, Abdelaal, Pedersen, Malmodin, Abrahamsson, Hutter, Godson, Brennan, Fändriks, le Roux and Docherty.]
Original languageEnglish
Article number757228
Pages (from-to)1-25
Number of pages25
JournalFrontiers in Endocrinology
Volume12
DOIs
Publication statusPublished - 26 Jan 2022

Bibliographical note

Funding Information:
We acknowledge local support received in the realization of these?studies from the UCD Biomedical Facility and the Research?Pathology and Genomics Core Facilities at the UCD Conway Institute. We also acknowledge the Genomics and Bioinformatics Core Facility platforms at the Sahlgrenska Academy, University of Gothenburg as well as the Swedish NMR Centre, University of Gothenburg. We thank Dr. Parker Wilson and Dr. Benjamin Humphreys for sharing human kidney single-nucleus RNA-sequencing data with us. Figures?1 and 12 were created with BioRender.com. We are grateful to Ludmilla Dellatorre Pessanha (ludmilla.pessanha@ucd.ie) for preparing the illustration of Roux-en-Y gastric bypass included in Figure?12.

Funding Information:
Funding support from the following agencies is acknowledged; Science Foundation Ireland (12/YI/B2480) to ClR, Swedish Medical Research Council (2015-02733) to LF, ClR, and ND, European Foundation for the Study of Diabetes/Boehringer Ingelheim European Diabetes Research Programme (BI 2017_3) to ClR and ND, and Science Foundation Ireland (15/ IA/3152 and 15/US/B3130) to CG and EB. EB is supported by a UCD Ad Astra Fellowship. WM’s contribution was performed within the Irish Clinical Academic Training (ICAT) Programme, supported by the Wellcome Trust and the Health Research Board (Grant Number 203930/B/16/Z), the Health Service Executive National Doctors Training and Planning, and the Health and Social Care, Research and Development Division, Northern Ireland.

Publisher Copyright:
Copyright © 2022 Martin, Chuah, Abdelaal, Pedersen, Malmodin, Abrahamsson, Hutter, Godson, Brennan, Fändriks, le Roux and Docherty.

Keywords

  • Endocrinology
  • bariatric surgery
  • diabetic kidney disease
  • transcriptome
  • metabolome
  • fatty acid oxidation
  • peroxisome
  • mitochondria
  • PPAR-alpha

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