A very-low-protein diet ameliorates advanced diabetic nephropathy through autophagy induction by suppression of the mTORC1 pathway in Wistar fatty rats, an animal model of type 2 diabetes and obesity

Kitada, Munehiro; Ogura, Yoshio; Suzuki, Taeko; Shu, Shi; Lee, Seon Myeong; Kanasaki, Keizo; Kume, Shinji; Koya, Daisuke

doi:10.1007/s00125-016-3925-4

Cited by 81 publications

(100 citation statements)

References 41 publications

(49 reference statements)

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“…Interestingly, a recent paper demonstrated that very low protein diet ameliorates advanced diabetic nephropathy (35), associated with suppression of p-S6 ribosomal protein (p-S6RP), which is in line with the data presented in this manuscript. We also observed upregulation of genes involved in lipogenesis and suppressed expression of the gluconeogenic gene, PEPCK in the kidney of MR mice compared to controls inferring improved insulin responsiveness.…”

Section: Discussionsupporting

confidence: 91%

Methionine restriction improves renal insulin signalling in aged kidneys

Grant

Lees

Forney

et al. 2016

Mechanisms of Ageing and Development

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Dietary methionine restriction (MR) leads to loss of adiposity, improved insulin sensitivity and lifespan extension. The possibility that dietary MR can protect the kidney from age-associated deterioration has not been addressed. Aged (10-month old) male and female mice were placed on a MR (0.172% methionine) or control diet (0.86% methionine) for 8-weeks and blood glucose, renal insulin signalling, and gene expression were assessed. Methionine restriction lead to decreased blood glucose levels compared to control-fed mice, and enhanced insulin-stimulated phosphorylation of PKB/Akt and S6 in kidneys, indicative of improved glucose homeostasis. Increased expression of lipogenic genes and downregulation of PEPCK were observed, suggesting that kidneys from MR-fed animals are more insulin sensitive. Interestingly, renal gene expression of the mitochondrial uncoupling protein UCP1 was upregulated in MR-fed animals, as were the anti-ageing and renoprotective genes Sirt1, FGF21, klotho, and β-klotho. This was associated with alterations in renal histology trending towards reduced frequency of proximal tubule intersections containing vacuoles in mice that had been on dietary MR for 190 days compared to control-fed mice, which exhibited a pre-diabetic status. Our results indicate that dietary MR may offer potential in ameliorating the renal functional decline related to ageing and other disorders associated with metabolic dysfunction by enhancing renal insulin sensitivity and renoprotective gene expression.

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Section: Discussionsupporting

confidence: 91%

Methionine restriction improves renal insulin signalling in aged kidneys

Grant

Lees

Forney

et al. 2016

Mechanisms of Ageing and Development

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“…The mean BPs indicate no obvious hypertension in both control lean and WF rats at 44 weeks of age. 62 Kidney and glomerular hypertrophy has been observed at 24 and 44 weeks of age, respectively. Histologically, WF rats exhibit increased glomerular basement thickening, foot process effacement of the podocytes, mesangial area expansion, tubulointerstitial inflammation, tubular cell damage, and tubulointerstitial fibrosis at 24 weeks.…”

Section: Wf Ratsmentioning

confidence: 97%

“…This strain develops obesity and obesity-related features, such as hyperinsulinemia and hyperlipidemia, in the same manner as ZF rats. [61][62][63] The diabetes-induced changes appear to be caused by the combination of a predisposition for diabetes in the WKY rat and fa-induced obesity. Because fa/fa homozygous animals are infertile, mating between fa/+ heterozygous animals is required to maintain the production of fa/fa homozygous strains.…”

Section: Rat Models Zucker Diabetic Fatty Rats and Wistar Fatty Ratsmentioning

confidence: 99%

“…However, the diabetic state of WF rats is mild compared to ZDF rats. In WF rats, increased albuminuria (a urinary albumin/Cr ratio of 2.3 ± 3.1 [control lean rats] vs. 118.5 ± 161.9 mg/mmol [WF rats]) and urinary liver-type fatty acid-binding protein excretion are observed by 24 weeks, and a markedly progressive increase in these urinary biomarkers develops through 44 weeks of age (a urinary albumin/Cr ratio of 52.9 ± 27.4 [control lean rats] vs. 1,377.0 ± 968.0 mg/mmol [WF rats]), 62 which is accompanied by increased plasma cystatin C levels. The mean BPs indicate no obvious hypertension in both control lean and WF rats at 44 weeks of age.…”

Section: Wf Ratsmentioning

confidence: 99%

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Rodent models of diabetic nephropathy: their utility and limitations

Kitada¹,

Ogura²,

Koya³

2016

IJNRD

Self Cite

187

129

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Diabetic nephropathy is the most common cause of end-stage renal disease. Therefore, novel therapies for the suppression of diabetic nephropathy must be developed. Rodent models are useful for elucidating the pathogenesis of diseases and testing novel therapies, and many type 1 and type 2 diabetic rodent models have been established for the study of diabetes and diabetic complications. Streptozotocin (STZ)-induced diabetic animals are widely used as a model of type 1 diabetes. Akita diabetic mice that have an Ins2+/C96Y mutation and OVE26 mice that overexpress calmodulin in pancreatic β-cells serve as a genetic model of type 1 diabetes. In addition, db/db mice, KK-Ay mice, Zucker diabetic fatty rats, Wistar fatty rats, Otsuka Long-Evans Tokushima Fatty rats and Goto-Kakizaki rats serve as rodent models of type 2 diabetes. An animal model of diabetic nephropathy should exhibit progressive albuminuria and a decrease in renal function, as well as the characteristic histological changes in the glomeruli and the tubulointerstitial lesions that are observed in cases of human diabetic nephropathy. A rodent model that strongly exhibits all these features of human diabetic nephropathy has not yet been developed. However, the currently available rodent models of diabetes can be useful in the study of diabetic nephropathy by increasing our understanding of the features of each diabetic rodent model. Furthermore, the genetic background and strain of each mouse model result in differences in susceptibility to diabetic nephropathy with albuminuria and the development of glomerular and tubulointerstitial lesions. Therefore, the validation of an animal model reproducing human diabetic nephropathy will significantly facilitate our understanding of the underlying genetic mechanisms that contribute to the development of diabetic nephropathy. In this review, we focus on rodent models of diabetes and discuss the utility and limitations of these models for the study of diabetic nephropathy.

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“…Diabetic nephropathy (DN), characterised by declining renal function, is the leading cause of end-stage renal disease (ESRD) in the Western world, and is associated with significant cardiovascular morbidity and mortality [10][11][12][13]. In recent studies, it has become clear that aldosterone should be considered a hormone with widespread unfavorable effects on the vasculature, the heart and the kidneys.…”

Section: Introductionmentioning

confidence: 99%