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

Files in This Item:
 File SizeFormat
Downloadfendo-12-757228.pdf19.63 MBAdobe PDF
Title: 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
Authors: Martin, William P.Chuah, Yeong H. D.Abdelaal, MahmoudHutter, MichaelaGodson, CatherineBrennan, Eoinle Roux, Carel W.Docherty, Neil G.et al.
Permanent link: http://hdl.handle.net/10197/12755
Date: 26-Jan-2022
Online since: 2022-02-03T14:32:00Z
Abstract: Background: 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. Methods: 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 (1H-NMR spectroscopy) responses were profiled and integrated. Transcripts were assigned to kidney cell types through in silico 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. Results: 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. Conclusions: 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.
Funding Details: Health Research Board
Health Service Executive
Science Foundation Ireland
University College Dublin
Wellcome Trust
Funding Details: Swedish Medical Research Council
European Foundation for the Study of Diabetes/Boehringer Ingelheim European Diabetes Research Programme
Health and Social Care, Research and Development Division, Northern Ireland
Type of material: Journal Article
Publisher: Frontiers Media
Journal: Frontiers in Endocrinology
Volume: 12
Copyright (published version): 2022 the Authors
Keywords: PreventionClinical researchGeneticsDiabetesObesityKidney diseaseDigestive diseasesRenal and urogenital
DOI: 10.3389/fendo.2021.757228
Language: en
Status of Item: Peer reviewed
ISSN: 1664-2392
This item is made available under a Creative Commons License: https://creativecommons.org/licenses/by/3.0/ie/
Appears in Collections:Conway Institute Research Collection
Medicine Research Collection

Show full item record

Page view(s)

275
Last Week
8
Last month
56
checked on May 21, 2022

Download(s)

41
checked on May 21, 2022

Google ScholarTM

Check

Altmetric


If you are a publisher or author and have copyright concerns for any item, please email research.repository@ucd.ie and the item will be withdrawn immediately. The author or person responsible for depositing the article will be contacted within one business day.