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Dietary Restriction and Medical Therapy Drives PPARα-Regulated Improvements in Early Diabetic Kidney Disease in Male Rats
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 replicate...
Autores principales: | , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7613831/ https://www.ncbi.nlm.nih.gov/pubmed/36259366 http://dx.doi.org/10.1042/CS20220205 |
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author | Martin, William P. Nair, Meera Chuah, Yeong H.D. Malmodin, Daniel Pedersen, Anders Abrahamsson, Sanna Hutter, Michaela Abdelaal, Mahmoud Elliott, Jessie A. Fearon, Naomi Eckhardt, Hans Godson, Catherine Brennan, Eoin P. Fändriks, Lars le Roux, Carel W. Docherty, Neil G. |
author_facet | Martin, William P. Nair, Meera Chuah, Yeong H.D. Malmodin, Daniel Pedersen, Anders Abrahamsson, Sanna Hutter, Michaela Abdelaal, Mahmoud Elliott, Jessie A. Fearon, Naomi Eckhardt, Hans Godson, Catherine Brennan, Eoin P. Fändriks, Lars le Roux, Carel W. Docherty, Neil G. |
author_sort | Martin, William P. |
collection | PubMed |
description | 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 (1)H-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, normalised 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 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 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. |
format | Online Article Text |
id | pubmed-7613831 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
record_format | MEDLINE/PubMed |
spelling | pubmed-76138312022-11-15 Dietary Restriction and Medical Therapy Drives PPARα-Regulated Improvements in Early Diabetic Kidney Disease in Male Rats Martin, William P. Nair, Meera Chuah, Yeong H.D. Malmodin, Daniel Pedersen, Anders Abrahamsson, Sanna Hutter, Michaela Abdelaal, Mahmoud Elliott, Jessie A. Fearon, Naomi Eckhardt, Hans Godson, Catherine Brennan, Eoin P. Fändriks, Lars le Roux, Carel W. Docherty, Neil G. Clin Sci (Lond) Article 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 (1)H-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, normalised 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 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 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. 2022-11-11 /pmc/articles/PMC7613831/ /pubmed/36259366 http://dx.doi.org/10.1042/CS20220205 Text en https://creativecommons.org/licenses/by/4.0/This work is licensed under a CC BY 4.0 (https://creativecommons.org/licenses/by/4.0/) International license. |
spellingShingle | Article Martin, William P. Nair, Meera Chuah, Yeong H.D. Malmodin, Daniel Pedersen, Anders Abrahamsson, Sanna Hutter, Michaela Abdelaal, Mahmoud Elliott, Jessie A. Fearon, Naomi Eckhardt, Hans Godson, Catherine Brennan, Eoin P. Fändriks, Lars le Roux, Carel W. Docherty, Neil G. Dietary Restriction and Medical Therapy Drives PPARα-Regulated Improvements in Early Diabetic Kidney Disease in Male Rats |
title | Dietary Restriction and Medical Therapy Drives PPARα-Regulated Improvements in Early Diabetic Kidney Disease in Male Rats |
title_full | Dietary Restriction and Medical Therapy Drives PPARα-Regulated Improvements in Early Diabetic Kidney Disease in Male Rats |
title_fullStr | Dietary Restriction and Medical Therapy Drives PPARα-Regulated Improvements in Early Diabetic Kidney Disease in Male Rats |
title_full_unstemmed | Dietary Restriction and Medical Therapy Drives PPARα-Regulated Improvements in Early Diabetic Kidney Disease in Male Rats |
title_short | Dietary Restriction and Medical Therapy Drives PPARα-Regulated Improvements in Early Diabetic Kidney Disease in Male Rats |
title_sort | dietary restriction and medical therapy drives pparα-regulated improvements in early diabetic kidney disease in male rats |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7613831/ https://www.ncbi.nlm.nih.gov/pubmed/36259366 http://dx.doi.org/10.1042/CS20220205 |
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