Methionine abrogates the renoprotective effect of a low-protein diet against diabetic kidney disease in obese rats with type 2 diabetes
Methionine abrogates the renoprotective effect of a low-protein diet against diabetic kidney disease in obese rats with type 2 diabetes
复制标题
DOI：
10.18632/aging.102902
复制
发表时间：
2020-03-15
期刊：
影响因子：
5.2
通讯作者：
Koya, Daisuke
中科院分区：
文献类型：
--
作者：
Kitada, Munehiro;Ogura, Yoshio;Koya, Daisuke
饮食干预，包括低蛋白饮食（LPD）和蛋氨酸（Met）限制，已显示出长寿，抗衰老和代谢健康的影响。我们以前报道过LPD对2型糖尿病和肥胖大鼠的糖尿病肾病（DKD）具有肾脏保护作用。然而，目前尚不清楚LPD的有益作用是否由低Met摄入介导，或者Met如何与DKD的发病机制相关。我们在此表明，在糖尿病肾脏中，Met与LPD的添加消除了由LPD诱导的有益作用，例如抗氧化应激、抗炎和抗纤维化。此外，肾小管细胞中S-腺苷甲硫氨酸（SAM）水平的增加，与甘氨酸N-甲基转移酶（Gnmt）表达的减少和非限制性Met摄入相关，有助于激活雷帕霉素复合物1（mTORC 1）的机制靶点和糖尿病肾脏中受损的自噬。此外，饥饿诱导的自噬在Gnmt敲除小鼠的肾皮质中被抑制，并且在培养的HK-2细胞中通过施用SAM也抑制了无氨基酸诱导的自噬。在糖尿病肾脏中，LPD可通过抑制mTORC 1和恢复自噬来发挥肾保护作用，自噬与低Met摄入导致的SAM水平降低相关。
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.