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

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

Ämnesord

MEDICIN OCH HÄLSOVETENSKAP  -- Klinisk medicin -- Endokrinologi och diabetes (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Clinical Medicine -- Endocrinology and Diabetes (hsv//eng)

Nyckelord

bariatric surgery

diabetic kidney disease

fatty acid oxidation

metabolome

mitochondria

peroxisome

PPAR-alpha

transcriptome

fenofibrate

messenger RNA

metformin

nuclear RNA

peroxisome proliferator activated receptor alpha

ramipril

rosuvastatin

triacylglycerol

animal experiment

animal model

animal tissue

Article

bioinformatics

controlled study

diabetic nephropathy

disease severity

down regulation

epithelium cell

Fontan procedure

gastric bypass surgery

gene expression

gene ontology

genetic transcription

glomerulus basement membrane

glycemic control

glycolysis

hemodynamics

hypertension

immunohistochemistry

kidney biopsy

kidney cortex tissue

lipid composition

lipid metabolism

male

metabolic regulation

metabolomics

mitochondrial biogenesis

mitochondrial respiration

morphometry

nonhuman

podocyte

prevalence

proteomics

proton nuclear magnetic resonance

quality control

rat

real time polymerase chain reaction

risk factor

RNA sequencing

Roux-en-Y gastric bypass

Sprague Dawley rat

transcription initiation

transcriptomics

transmission electron microscopy

treatment response

upregulation

Zucker diabetic fatty rat

Publikations- och innehållstyp

ref (ämneskategori)

art (ämneskategori)