Manipulating Sirtuin 3 pathway ameliorates renal damage in experimental diabetes.
Albuminuria
/ prevention & control
Animals
Anti-Inflammatory Agents
/ therapeutic use
Antioxidants
/ therapeutic use
Biphenyl Compounds
/ therapeutic use
Cytokines
/ metabolism
Diabetes Mellitus, Experimental
/ drug therapy
Diabetes Mellitus, Type 2
/ drug therapy
Diabetic Nephropathies
/ drug therapy
Kidney Glomerulus
/ pathology
Lignans
/ therapeutic use
Male
Mice
Mice, Obese
Mitochondria
/ metabolism
Nicotinamide Phosphoribosyltransferase
/ metabolism
Oxidative Stress
/ drug effects
Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
/ metabolism
Podocytes
/ drug effects
Reactive Oxygen Species
/ metabolism
Sirtuin 3
/ metabolism
Superoxide Dismutase
/ metabolism
Journal
Scientific reports
ISSN: 2045-2322
Titre abrégé: Sci Rep
Pays: England
ID NLM: 101563288
Informations de publication
Date de publication:
21 05 2020
21 05 2020
Historique:
received:
10
01
2020
accepted:
14
04
2020
entrez:
23
5
2020
pubmed:
23
5
2020
medline:
15
12
2020
Statut:
epublish
Résumé
More effective treatments for diabetic nephropathy remain a major unmet clinical need. Increased oxidative stress is one of the most important pathological mechanisms that lead to kidney damage and functional impairment induced by diabetes. Sirtuin 3 (SIRT3) is the main mitochondrial deacetylase and critically regulates cellular reactive oxygen species (ROS) production and detoxification. Honokiol is a natural biphenolic compound that, by activating mitochondrial SIRT3, can carry out anti-oxidant, anti-inflammatory and anti-fibrotic activities. Here, we sought to investigate the renoprotective effects of honokiol in BTBR ob/ob mice with type 2 diabetes. Diabetic mice were treated with vehicle or honokiol between the ages of 8 and 14 weeks. Wild-type mice served as controls. Renal Sirt3 expression was significantly reduced in BTBR ob/ob mice, and this was associated with a reduction in its activity and increased ROS levels. Selective activation of SIRT3 through honokiol administration translated into the attenuation of albuminuria, amelioration of glomerular damage, and a reduction in podocyte injury. SIRT3 activation preserved mitochondrial wellness through the activation of SOD2 and the restoration of PGC-1α expression in glomerular cells. Additionally, the protective role of SIRT3 in glomerular changes was associated with enhanced tubular Sirt3 expression and upregulated renal Nampt levels, indicating a possible tubule-glomerulus retrograde interplay, which resulted in improved glomerular SIRT3 activity. Our results demonstrate the hitherto unknown renoprotective effect of SIRT3 against diabetic glomerular disease and suggest that the pharmacological modulation of SIRT3 activity is a possible novel approach to treating diabetic nephropathy.
Identifiants
pubmed: 32439965
doi: 10.1038/s41598-020-65423-0
pii: 10.1038/s41598-020-65423-0
pmc: PMC7242337
doi:
Substances chimiques
Anti-Inflammatory Agents
0
Antioxidants
0
Biphenyl Compounds
0
Cytokines
0
Lignans
0
Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
0
Ppargc1a protein, mouse
0
Reactive Oxygen Species
0
honokiol
11513CCO0N
Superoxide Dismutase
EC 1.15.1.1
Nicotinamide Phosphoribosyltransferase
EC 2.4.2.12
nicotinamide phosphoribosyltransferase, mouse
EC 2.4.2.12
Sirtuin 3
EC 3.5.1.-
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
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