1. 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
- Author
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Munehiro Kitada, Shi Sen, Keizo Kanasaki, Daisuke Koya, Shinji Kume, Taeko Suzuki, Seon Myeong Lee, and Yoshio Ogura
- Subjects
Male ,0301 basic medicine ,medicine.medical_specialty ,Endocrinology, Diabetes and Metabolism ,medicine.medical_treatment ,mTORC1 ,Type 2 diabetes ,Mechanistic Target of Rapamycin Complex 1 ,Biology ,Real-Time Polymerase Chain Reaction ,Diabetic nephropathy ,03 medical and health sciences ,Animal model ,Microscopy, Electron, Transmission ,Low-protein diet ,hemic and lymphatic diseases ,Internal medicine ,Autophagy ,Diet, Protein-Restricted ,Internal Medicine ,medicine ,Animals ,Diabetic Nephropathies ,Obesity ,Rats, Wistar ,TOR Serine-Threonine Kinases ,medicine.disease ,Immunohistochemistry ,Rats ,Disease Models, Animal ,030104 developmental biology ,Endocrinology ,Diabetes Mellitus, Type 2 ,Multiprotein Complexes ,Molecular mechanism - Abstract
The efficacy of a low-protein diet (LPD) on diabetic nephropathy is controversial. We aimed to investigate the renoprotective effects of an LPD and the underlying molecular mechanism in a rat model of type 2 diabetes and obesity.Diabetic male Wistar fatty (fa/fa) rats (WFRs) were treated with a standard diet (23.84% protein) or an LPD (5.77% protein) for 20 weeks from 24 weeks of age. We investigated the effect of the LPD on renal function, fibrosis, tubular cell damage, inflammation, mitochondrial morphology of proximal tubular cells (PTCs), apoptosis, autophagy and activation of mammalian target of rapamycin complex 1 (mTORC1).Kidney weight, albuminuria, excretion of urinary liver-type fatty acid binding protein, levels of plasma cystatin C and changes in renal histology, including fibrosis, tubular cell damage and inflammation, were aggravated in WFRs compared with non-diabetic Wistar lean rats (WLRs). Fragmented and swelling mitochondria accumulated in PTCs and apoptosis were enhanced in the kidney of WFRs. Immunohistochemical staining of p62 and p-S6 ribosomal protein (p-S6RP) in the tubular lesions of WFRs was increased compared with WLRs. The LPD intervention clearly ameliorated damage as shown by the assessment of renal function and histology, particularly tubulointerstitial damage in diabetic kidneys. Additionally, the 5.77% LPD, but not the 11.46% LPD, significantly suppressed p-S6RP levels and increased microtubule-associated protein light chain 3-II levels in the renal cortex. The LPD intervention partially decreased HbA1c levels in WFRs, and no differences in mean BP were observed among any of the groups.A very-low-protein diet improved advanced diabetic renal injuries, including tubulointerstitial damage, by restoring autophagy through the suppression of the mTORC1 pathway.
- Published
- 2016