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. 2011:2011:908185.
doi: 10.1155/2011/908185. Epub 2011 Sep 22.

Dietary restriction ameliorates diabetic nephropathy through anti-inflammatory effects and regulation of the autophagy via restoration of Sirt1 in diabetic Wistar fatty (fa/fa) rats: a model of type 2 diabetes

Munehiro Kitada  1 , Ai Takeda, Takako Nagai, Hiroki Ito, Keizo Kanasaki, Daisuke Koya
Affiliations

Dietary restriction ameliorates diabetic nephropathy through anti-inflammatory effects and regulation of the autophagy via restoration of Sirt1 in diabetic Wistar fatty (fa/fa) rats: a model of type 2 diabetes

Munehiro Kitada et al. Exp Diabetes Res. 2011.

Abstract

Aim: Despite the beneficial effects of dietary restriction (DR) on lifespan, age-related diseases, including diabetes and cardiovascular diseases, its effects on type 2 diabetic nephropathy remain unknown. This study examined the renoprotective effects of DR in Wistar fatty (fa/fa) rats (WFRs).

Methods: WFRs were treated with DR (40% restriction) for 24 weeks. Urinary albumin excretion, creatinine clearance, renal histologies, acetylated-NF-κB (p65), Sirt1 protein expression, and p62/Sqstm 1 accumulation in the renal cortex, as well as electron microscopic observation of mitochondrial morphology and autophagosomes in proximal tubular cells were estimated.

Results: DR ameliorated renal abnormalities including inflammation in WFRs. The decrease in Sirt1 levels, increase in acetylated-NF-κB, and impaired autophagy in WFRs were improved by DR.

Conclusions: DR exerted anti-inflammatory effects and improved the dysregulation of autophagy through the restoration of Sirt1 in the kidneys of WFRs, which resulted in the amelioration of renal injuries in type 2 diabetes.

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Figures

Figure 1
Figure 1
DR ameliorates urinary albumin excretion (a) and creatinine clearance (Ccr) (b) in Wistar fatty rats (WFRs). Treatment with DR reduced urinary albumin excretion and improved Ccr in WFRs. Data are means ± SD (n = 9 − 11, # P < 0.01 versus other groups, ## P < 0.05 versus other groups).
Figure 2
Figure 2
DR ameliorates mesangial expansion and renal fibrosis in WFRs. ((a)-(A) through (D)) Representative photomicrographs of PAS-stained kidney sections from four groups of rats. Data are the results of independent experiments in each group with six rats per group. Original magnification, ×400. (b) Quantitative assessment of the mesangial matrix area in the four groups of rats. Data are means ± SD. (n = 6, # P < 0.01 versus other groups). Treatment with DR reduced glomerular and interstitial fibrosis in WFRs. ((a)-(E) through (H), (I) through (L)) Representative photomicrographs of Masson-Trichrome staining in the four groups of rats. Data are the results of independent experiments in each group with six rats per group. Original magnification, ×400 for glomerular fibrosis and ×100 for interstitial fibrosis. (c) and (d) Quantitative assessment of fibrosis in the four groups of rats. Data are means ± SD (n = 6, # P < 0.01 versus other groups).
Figure 3
Figure 3
TGF-β, fibronectin, and collagen IV mRNA expression levels in the kidney. The mRNA expression levels of TGF-β (a), fibronectin (b), and collagen IV (c) were quantified using real-time PCR and expressed as fold increases from Wistar lean rats (WLRs). Data are means ± SD (n = 9 − 11, # P < 0.05 versus other groups).
Figure 4
Figure 4
Treatment with DR suppresses the number of ED-1-positive cells in the kidney of WFRs. ((a)-(A) through (H)) Representative photomicrographs of renal ED-1-positive cells in the four groups of rats. Data are the results of independent experiments in each group with six mice per group. Original magnification, ×400 for glomerular ED-1 staining and ×100 for tubule-interstitial ED-1 staining. (b) and (c) ED-1-positive cells in glomerular and tubulointerstitial lesions. Data are means ± SD (n = 6, # P < 0.05  versus other groups, ## P < 0.01 versus other groups).
Figure 5
Figure 5
MCP-1, ICAM-1, and VCAM-1 mRNA expression levels in the kidney. The mRNA expression levels of MCP-1 (a), ICAM-1 (b), and VCAM-1 (c) were quantified using real-time PCR and expressed as fold increases from Wistar fatty rats. Data are means ± SD (n = 9 − 11, # P < 0.05 versus other groups).
Figure 6
Figure 6
Acetylated-NF-κB (p65) and Sirt1 expression in the kidney. (a) Representative immunoblots of Sirt1, acetylated-NF-κB (p65), and NF-κB in protein extracts from the kidneys of rats of each group. Actin was loaded as an internal control. (b) Quantitative analysis of acetylated-NF-κB (p65) protein expression. (c) Quantitative analysis of Sirt1 protein expression. Data are means ± SD (n = 6, # P < 0.01 versus other groups, ## P < 0.05 versus other groups).
Figure 7
Figure 7
p62/Sqptm1 accumulation and electron microscopy in the kidney. (a) Representative immunoblots of p62/sequestosome 1 (Sqptm1) in protein extracts from the kidneys from rats of each group. Actin was loaded as an internal control. Data are means ± SD (n = 6, # P < 0.01 versus other groups). (b) Quantitative analysis of p62/Sqptm1expression. Data are means ± SD (n = 6, # P < 0.05 versus other groups). (c) Representative micrographs of proximal tubular cells from the, four groups of rats. Scale bar = 1 μm (n = 3).
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