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.
Highlights
Diabetic kidney disease (DKD) is recognized as the leading cause of end-stage renal disease (ESRD)
We demonstrated that the addition of Met to the low-protein diet (LPD) at the same level as the standard diet (STD) clearly abrogated the renoprotective effect of the LPD on diabetes-induced renal injuries, including inflammation, mitochondrial abnormality and fibrosis
Recent reports have shown that a LPD could exert beneficial effects on longevity and metabolic health [26]
Summary
Diabetic kidney disease (DKD) is recognized as the leading cause of end-stage renal disease (ESRD). The degree of tubulointerstitial damage rather than glomerular damage is predictive of a decline in renal function in patients with chronic kidney disease (CKD), including DKD [1, 2]. Protecting renal tubular cells against cellular stress preserves renal function. In the pathogenesis of DKD, renal tubular damage and tubulointerstitial fibrosis play a crucial role in glomerular damage, which is called “diabetic tubulopathy” [3]. Aging is a universal process that affects all organs, and a gradual age-related decline in renal function, which is accompanied by an increase in histological renal tubulointerstitial and glomerular fibrosis, is observed [4, 5].
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