Methionine Abrogates the Reno-Protective Effect of a Low-Protein Diet Against Diabetic Kidney Disease in Obese Rats with Type 2 Diabetes

Abstract

Background: Dietary interventions, including a low-protein diet (LPD) and methionine (Met) restriction, has shown longevity and metabolic health. LPD has a reno-protective effect against diabetic kidney disease (DKD) in rats with type 2 diabetes and obesity; however, it is unclear whether the beneficial effect of LPD is mediated by a low-Met intake. Methods: Rats were divided into four groups at 24 weeks of age: 1) non-diabetic Wistar lean (fa/-) rats fed a standard diet including 0.64% Met (STD) (Control); 2) Wistar fatty (fa/fa) rats with type 2 diabetes/obesity (WFRs) fed STD (0.64% Met) (Diabetes); 3) WFRs fed LPD (0.15% Met) (LPD); and 4) WFRs fed LP+Met (0.64% Met) (LP+Met). The dietary intervention was performed for 20 weeks. Findings: Accumulation of S-adenosylmethionine (SAM) in renal tubular cells of diabetic rats, associated with reduced glycine Nmethyltransferase (Gnmt) expression, led to mechanistic target of rapamycin complex1 (mTORC1) activation and impaired autophagy, resulting in the progression of DKD through mitochondrial abnormalities, oxidative stress, inflammation, tubular cell damage and tubulointerstitial fibrosis. Additionally, cystathionine γ-lyase (CGL) expression was decreased in the diabetic renal cortex. LPD reversed all of these alterations of the diabetic kidney; however, the LP+Met diet abrogated the effects of LPD in diabetic rats. Furthermore, LPD partially improved the diabetic state, while the LP+Met diet exacerbated it and was accompanied by changes in the LPD-induced expression of plasma fibroblast growth factor 21 (FGF21). Interpretation: LPD could exert a reno-protective effect through low-Met intake-mediated suppression of mTORC1 and restored autophagy, which is associated with a decrease in the accumulation of SAM due to reduced expression of Gnmt in diabetic kidneys. Funding Statement: This work was financially supported through a Grant-in-Aid for Scientific Research KAKENHI (C) (24591218), a grant for collaborative research with Kowa Hakko Kirin to MK. Declaration of Interests: Boehringer Ingelheim, Mitsubishi Tanabe Pharma, Kyowa Hakko Kirin, Taisho Toyama Pharmaceutical Co. and Ono Pharmaceutical Co. contributed to establishing the Division of Anticipatory Molecular Food Science and Technology. The authors declare that there is no duality of interest associated with this manuscript. Ethics Approval Statement: The Research Center for Animal Life Science of Kanazawa Medical University approved all experiments, and all experiments were performed in accordance with the relevant guidelines and regulations.