Research Paper Volume 12, Issue 5 pp 4489—4505

Methionine abrogates the renoprotective effect of a low-protein diet against diabetic kidney disease in obese rats with type 2 diabetes

Munehiro Kitada 1, 2, , Yoshio Ogura 1, , Itaru Monno 1, , Jing Xu 1, , Daisuke Koya 1, 2, ,

  • 1 Department of Diabetology and Endocrinology, Kanazawa Medical University, Uchinada, Ishikawa, Japan
  • 2 Division of Anticipatory Molecular Food Science and Technology, Medical Research Institute, Kanazawa Medical University, Uchinada, Ishikawa, Japan

received: December 4, 2019 ; accepted: January 27, 2020 ; published: March 6, 2020 ;

https://doi.org/10.18632/aging.102902
How to Cite

Copyright © 2020 Kitada et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

Dietary interventions, including a low-protein diet (LPD) and methionine (Met) restriction, have shown longevity, anti-aging and metabolic health effects. We previously reported that the LPD has a renoprotective effect against diabetic kidney disease (DKD) in rats with type 2 diabetes and obesity. However, it is unclear whether the beneficial effect of the LPD is mediated by low-Met intake or how Met is related to the pathogenesis for DKD. We herein show that the addition of Met with the LPD abrogates the beneficial effects induced by the LPD such as anti-oxidative stress, anti-inflammation and anti-fibrosis, in diabetic kidney. Additionally, the increased levels of S-adenosylmethionine (SAM) in renal tubular cells, which are associated with the reduced expression of glycine N-methyltransferase (Gnmt) and non-restricted Met intake, contributes to the activation of mechanistic target of rapamycin complex 1 (mTORC1) and impaired autophagy, in diabetic kidney. Moreover, starvation-induced autophagy was suppressed in renal cortex of Gnmt null mice and amino acid free-induced autophagy was also suppressed by administration of SAM in cultured HK-2 cells. A LPD could exert a renoprotective effect through the suppression of mTORC1 and restoration of autophagy, which is associated with reduced levels of SAM due to low-Met intake, in diabetic kidney.

Abbreviations

LPD: low-protein diet; LP: low protein; Met: methionine; T-CHO: total cholesterol; TG: triglyceride; FGF21: fibroblast growth factor 21; Cr: creatinine; L-FABP: liver-type fatty acid binding protein; MT: Masson’s trichrome; PAS: Periodic Acid Schiff; Kim-1: kidney injury molecule-1; Tnf-α: tumor necrosis factor-α; Gnmt: glycine-N-methyltransferase; SAM: S-adenosylmethionine; LCMT1: leucine carboxyl methyltransferase 1; PP2A: protein phosphatase 2A; mTORC1: mechanistic target of rapamycin complex 1; p-S6RP: phospho-S6 ribosomal protein; PTCs: proximal tubular cells; TEM: transmission electron microscopy; 8-OHdG: 8-hydroxy-2'- deoxyguanosine.