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Dietary restriction...
Dietary restriction and medical therapy drive PPARα-regulated improvements in early diabetic kidney disease in male rats
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Martin, William P. (author)
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Nair, Meera (author)
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Chuah, Yeong H.D. (author)
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- Malmodin, Daniel, 1974 (author)
- Gothenburg University,Göteborgs universitet,Svenskt NMR-centrum vid Göteborgs universitet,Swedish NMR Centre at Göteborg University
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- Pedersen, Anders (author)
- Gothenburg University,Göteborgs universitet,Svenskt NMR-centrum vid Göteborgs universitet,Swedish NMR Centre at Göteborg University
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- Abrahamsson, Sanna (author)
- Gothenburg University,Göteborgs universitet,Core Facilities, Bioinformatics,Core Facilities, Bioinformatics
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Hutter, Michaela (author)
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Abdelaal, Mahmoud (author)
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Elliott, Jessie A. (author)
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Fearon, Naomi (author)
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Eckhardt, Hans (author)
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Godson, Catherine (author)
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Brennan, Eoin P. (author)
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- Fändriks, Lars, 1956 (author)
- Gothenburg University,Göteborgs universitet,Institutionen för kliniska vetenskaper,Institute of Clinical Sciences
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le Roux, Carel W. (author)
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Docherty, Neil G. (author)
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(creator_code:org_t)
- 2022
- 2022
- English.
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In: Clinical science (London, England : 1979). - 1470-8736. ; 136:21, s. 1485-1511
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Abstract
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- 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.
Subject headings
- NATURVETENSKAP -- Biologi -- Biofysik (hsv//swe)
- NATURAL SCIENCES -- Biological Sciences -- Biophysics (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Endokrinologi och diabetes (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Endocrinology and Diabetes (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Fysiologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Physiology (hsv//eng)
Keyword
- diabetic nephropathy
- fatty acid oxidation
- peroxisome proliferator-activated receptors
- preclinical
- transcriptomics
- weight loss
Publication and Content Type
- ref (subject category)
- art (subject category)
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- By the author/editor
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Martin, William ...
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Nair, Meera
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Chuah, Yeong H.D ...
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Malmodin, Daniel ...
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Pedersen, Anders
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Abrahamsson, San ...
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show more...
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Hutter, Michaela
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Abdelaal, Mahmou ...
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Elliott, Jessie ...
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Fearon, Naomi
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Eckhardt, Hans
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Godson, Catherin ...
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Brennan, Eoin P.
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Fändriks, Lars, ...
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le Roux, Carel W ...
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Docherty, Neil G ...
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show less...
- About the subject
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- NATURAL SCIENCES
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NATURAL SCIENCES
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and Biological Scien ...
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and Biophysics
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Clinical Medicin ...
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and Endocrinology an ...
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Basic Medicine
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and Physiology
- Articles in the publication
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Clinical science ...
- By the university
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University of Gothenburg