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Sirtuin 3 Deficiency Aggravates Kidney Disease in Response to High-Fat Diet through Lipotoxicity-Induced Mitochondrial Damage

Sirtuin 3 (SIRT3) is the primary mitochondrial deacetylase that controls the antioxidant pathway and energy metabolism. We previously found that renal Sirt3 expression and activity were reduced in mice with type 2 diabetic nephropathy associated with oxidative stress and mitochondrial abnormalities...

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Autores principales: Locatelli, Monica, Macconi, Daniela, Corna, Daniela, Cerullo, Domenico, Rottoli, Daniela, Remuzzi, Giuseppe, Benigni, Ariela, Zoja, Carlamaria
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9368634/
https://www.ncbi.nlm.nih.gov/pubmed/35955472
http://dx.doi.org/10.3390/ijms23158345
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author Locatelli, Monica
Macconi, Daniela
Corna, Daniela
Cerullo, Domenico
Rottoli, Daniela
Remuzzi, Giuseppe
Benigni, Ariela
Zoja, Carlamaria
author_facet Locatelli, Monica
Macconi, Daniela
Corna, Daniela
Cerullo, Domenico
Rottoli, Daniela
Remuzzi, Giuseppe
Benigni, Ariela
Zoja, Carlamaria
author_sort Locatelli, Monica
collection PubMed
description Sirtuin 3 (SIRT3) is the primary mitochondrial deacetylase that controls the antioxidant pathway and energy metabolism. We previously found that renal Sirt3 expression and activity were reduced in mice with type 2 diabetic nephropathy associated with oxidative stress and mitochondrial abnormalities and that a specific SIRT3 activator improved renal damage. SIRT3 is modulated by diet, and to assess whether Sirt3 deficiency aggravates mitochondrial damage and accelerates kidney disease in response to nutrient overloads, wild-type (WT) and Sirt3(−/−) mice were fed a high-fat-diet (HFD) or standard diet for 8 months. Sirt3(−/−) mice on HFD exhibited earlier and more severe albuminuria compared to WT mice, accompanied by podocyte dysfunction and glomerular capillary rarefaction. Mesangial matrix expansion, tubular vacuolization and inflammation, associated with enhanced lipid accumulation, were more evident in Sirt3(−/−) mice. After HFD, kidneys from Sirt3(−/−) mice showed more oxidative stress than WT mice, mitochondria ultrastructural damage in tubular cells, and a reduction in mitochondrial mass and energy production. Our data demonstrate that Sirt3 deficiency renders mice more prone to developing oxidative stress and mitochondrial abnormalities in response to HFD, resulting in more severe kidney diseases, and this suggests that mitochondria protection may be a method to prevent HFD-induced renal injury.
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spelling pubmed-93686342022-08-12 Sirtuin 3 Deficiency Aggravates Kidney Disease in Response to High-Fat Diet through Lipotoxicity-Induced Mitochondrial Damage Locatelli, Monica Macconi, Daniela Corna, Daniela Cerullo, Domenico Rottoli, Daniela Remuzzi, Giuseppe Benigni, Ariela Zoja, Carlamaria Int J Mol Sci Article Sirtuin 3 (SIRT3) is the primary mitochondrial deacetylase that controls the antioxidant pathway and energy metabolism. We previously found that renal Sirt3 expression and activity were reduced in mice with type 2 diabetic nephropathy associated with oxidative stress and mitochondrial abnormalities and that a specific SIRT3 activator improved renal damage. SIRT3 is modulated by diet, and to assess whether Sirt3 deficiency aggravates mitochondrial damage and accelerates kidney disease in response to nutrient overloads, wild-type (WT) and Sirt3(−/−) mice were fed a high-fat-diet (HFD) or standard diet for 8 months. Sirt3(−/−) mice on HFD exhibited earlier and more severe albuminuria compared to WT mice, accompanied by podocyte dysfunction and glomerular capillary rarefaction. Mesangial matrix expansion, tubular vacuolization and inflammation, associated with enhanced lipid accumulation, were more evident in Sirt3(−/−) mice. After HFD, kidneys from Sirt3(−/−) mice showed more oxidative stress than WT mice, mitochondria ultrastructural damage in tubular cells, and a reduction in mitochondrial mass and energy production. Our data demonstrate that Sirt3 deficiency renders mice more prone to developing oxidative stress and mitochondrial abnormalities in response to HFD, resulting in more severe kidney diseases, and this suggests that mitochondria protection may be a method to prevent HFD-induced renal injury. MDPI 2022-07-28 /pmc/articles/PMC9368634/ /pubmed/35955472 http://dx.doi.org/10.3390/ijms23158345 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Locatelli, Monica
Macconi, Daniela
Corna, Daniela
Cerullo, Domenico
Rottoli, Daniela
Remuzzi, Giuseppe
Benigni, Ariela
Zoja, Carlamaria
Sirtuin 3 Deficiency Aggravates Kidney Disease in Response to High-Fat Diet through Lipotoxicity-Induced Mitochondrial Damage
title Sirtuin 3 Deficiency Aggravates Kidney Disease in Response to High-Fat Diet through Lipotoxicity-Induced Mitochondrial Damage
title_full Sirtuin 3 Deficiency Aggravates Kidney Disease in Response to High-Fat Diet through Lipotoxicity-Induced Mitochondrial Damage
title_fullStr Sirtuin 3 Deficiency Aggravates Kidney Disease in Response to High-Fat Diet through Lipotoxicity-Induced Mitochondrial Damage
title_full_unstemmed Sirtuin 3 Deficiency Aggravates Kidney Disease in Response to High-Fat Diet through Lipotoxicity-Induced Mitochondrial Damage
title_short Sirtuin 3 Deficiency Aggravates Kidney Disease in Response to High-Fat Diet through Lipotoxicity-Induced Mitochondrial Damage
title_sort sirtuin 3 deficiency aggravates kidney disease in response to high-fat diet through lipotoxicity-induced mitochondrial damage
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9368634/
https://www.ncbi.nlm.nih.gov/pubmed/35955472
http://dx.doi.org/10.3390/ijms23158345
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