Abstract
BackgroundA high-calorie (HC) diet induces renal injury and promotes aging, and calorie restriction (CR) may ameliorate these responses. However, the effects of long-term HC and CR on renal damage and aging have been not fully determined. Autophagy plays a crucial role in removing protein aggregates and damaged organelles to maintain intracellular homeostasis and function. The role of autophagy in HC-induced renal damage is unknown.MethodsWe evaluated the expression of LC3/Atg8 as a marker of the autophagosome; p62/SQSTM1; polyubiquitin aggregates as markers of autophagy flux; Ambra1, PINK1, Parkin and Bnip3 as markers of mitophagy; 8-hydroxydeoxyguanosine (8-OHdG) as a marker of DNA oxidative damage; and p16 as a marker of organ aging by western blot and immunohistochemical staining in the kidneys of 24-month-old Fischer 344 rats. We also observed mitochondrial structure and autolysosomes by transmission electron microscopy.ResultsExpression of the autophagosome formation marker LC3/Atg8 and markers of mitochondrial autophagy (mitophagy) were markedly decreased in the kidneys of the HC group, and markedly increased in CR kidneys. p62/SQSTM1 and polyubiquitin aggregates increased in HC kidneys, and decreased in CR kidneys. Transmission electron microscopy demonstrated that HC kidneys showed severe abnormal mitochondrial morphology with fewer autolysosomes, while CR kidneys exhibited normal mitochondrial morphology with numerous autolysosomes. The level of 8-hydroxydeoxyguanosine was increased in HC kidneys and decreased in CR kidneys. Markers of aging, such as p16 and senescence-associated-galactosidase, were increased significantly in the HC group and decreased significantly in the CR group.ConclusionThe study firstly suggests that HC diet inhibits renal autophagy and aggravates renal oxidative damage and aging, while CR enhances renal autophagy and ameliorates oxidative damage and aging in the kidneys.
Highlights
Diet has been long recognized as a modulator of kidney health in both humans and experimental models [1,2]
For the first time, we investigated the effect of a long-term (20-month) HC diet or calorie restriction (CR) on mitochondrial ultrastructure and the expression of light chain 3 (LC3)/Atg8; p62/sequestosome 1 (SQSTM1) and polyubiquitin aggregates; Ambra1, PTEN-induced kinase 1 (PINK1), Parkin and Bnip3; 8-hydroxydeoxyguanosine (8-OHdG); and p16 in the kidneys of 24-month-old male Fischer 344 rats
LC3-II is the only protein marker that is reliably associated with completed autophagosomes, but it is localized to phagophores
Summary
Diet has been long recognized as a modulator of kidney health in both humans and experimental models [1,2]. Calorie restriction (CR) can retard the progression of many age-associated molecular, physiological, and pathological processes which occur in tissues with high oxidative demand, such as kidney [3,4,5] skeletal muscle [6], heart [7] and brain [8]. Chronic progressive nephropathy was effectively reduced by restricted caloric intake [9]. A high-calorie (HC) diet induces renal injury and promotes aging, and calorie restriction (CR) may ameliorate these responses. The effects of long-term HC and CR on renal damage and aging have been not fully determined. The role of autophagy in HC-induced renal damage is unknown
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