Dietary restriction and medical therapy drives PPARα-regulated improvements in early diabetic kidney disease in male rats

William P. Martin, Meera Nair, Yeong H.D. Chuah, Daniel Malmodin, Anders Pedersen, Sanna Abrahamsson, Michaela Hutter, Mahmoud Abdelaal, Jessie A. Elliott, Naomi Fearon, Hans Eckhardt, Catherine Godson, Eoin P. Brennan, Lars Fändriks, Carel W. le Roux, Neil G. Docherty

Research output: Contribution to journalArticlepeer-review

Abstract

The attenuation of diabetic kidney disease (DKD) by metabolic surgery is enhanced by pharmacotherapy promoting renal fatty acid oxidation (FAO). Using the Zucker Diabetic Fatty and Zucker Diabetic Sprague Dawley rat models of DKD, we conducted studies to determine if these effects could be replicated with a non-invasive bariatric mimetic intervention. Metabolic control and renal injury were compared in rats undergoing a dietary restriction plus medical therapy protocol (DMT; fenofibrate, liraglutide, metformin, ramipril, and rosuvastatin) and ad libitum-fed controls. The global renal cortical transcriptome and urinary 1H-NMR metabolomic profiles were also compared. Kidney cell type-specific and medication-specific transcriptomic responses were explored through in silico deconvolution. Transcriptomic and metabolomic correlates of improvements in kidney structure were defined using a molecular morphometric approach. The DMT protocol led to ∼20% weight loss, normalized metabolic parameters and was associated with reductions in indices of glomerular and proximal tubular injury. The transcriptomic response to DMT was dominated by changes in fenofibrate- and peroxisome proliferator-activated receptor-α (PPARα)-governed peroxisomal and mitochondrial FAO transcripts localizing to the proximal tubule. DMT induced urinary excretion of PPARα-regulated metabolites involved in nicotinamide metabolism and reversed DKD-associated changes in the urinary excretion of tricarboxylic acid (TCA) cycle intermediates. FAO transcripts and urinary nicotinamide and TCA cycle metabolites were moderately to strongly correlated with improvements in glomerular and proximal tubular injury. Weight loss plus pharmacological PPARα agonism is a promising means of attenuating DKD.
Original languageEnglish
Pages (from-to)1485-1511
Number of pages27
JournalClinical Science
Volume136
Issue number21
Early online date19 Oct 2022
DOIs
Publication statusPublished (in print/issue) - 3 Nov 2022

Bibliographical note

This work was supported by the Science Foundation Ireland [grant number 12/YI/B2480 (to C.W.lR.)]; Swedish Medical Research Council [grant number 2015-02733 (to L.F., C.W.lR., and N.G.D.)]; European Foundation for the Study of Diabetes/Boehringer Ingelheim European Diabetes Research Programme [grant number BI 2017 3 (to C.W.lR. and N.G.D.)]; Science Foundation Ireland [grant numbers 15/IA/3152 and 15/US/B3130 (to C.G. and E.P.B.)]; UCD Ad Astra Fellowship (to E.P.B.); the Irish Clinical Academic Training (ICAT) Programme (to W.P.M.); the Wellcome Trust (to W.P.M.); the Health Research Board [grant Number 203930/B/16/Z (to W.P.M.)]; the Health Service Executive National Doctors Training and Planning; the Health and Social Care, Research and Development Division, Northern Ireland; the Wellcome Trust [grant Number 203930/B/16/Z (in part)]. For the purpose of open access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission.

Keywords

  • General Medicine
  • Niacinamide
  • Peroxisome Proliferator-activated Receptors
  • Diabetic Nephropathies
  • Weight loss
  • Rats
  • Male
  • PPAR alpha
  • Diabetes Mellitus
  • Rats, Sprague-Dawley
  • Kidney
  • Fenofibrate
  • Rats, Zucker
  • Animals
  • Transcriptomics
  • Weight Loss
  • Diabetic nephropathy
  • Fatty Acid Oxidation
  • Preclinical
  • peroxisome proliferator-activated receptors
  • preclinical
  • transcriptomics
  • weight loss
  • fatty acid oxidation
  • diabetic nephropathy

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