Abstract
A low-protein diet supplemented with ketoacids maintains nutritional status in patients with diabetic nephropathy. The activation of autophagy has been shown in the skeletal muscle of diabetic and uremic rats. This study aimed to determine whether a low-protein diet supplemented with ketoacids improves muscle atrophy and decreases the increased autophagy observed in rats with type 2 diabetic nephropathy. In this study, 24-week-old Goto-Kakizaki male rats were randomly divided into groups that received either a normal protein diet (NPD group), a low-protein diet (LPD group) or a low-protein diet supplemented with ketoacids (LPD+KA group) for 24 weeks. Age- and weight-matched Wistar rats served as control animals and received a normal protein diet (control group). We found that protein restriction attenuated proteinuria and decreased blood urea nitrogen and serum creatinine levels. Compared with the NPD and LPD groups, the LPD+KA group showed a delay in body weight loss, an attenuation in soleus muscle mass loss and a decrease of the mean cross-sectional area of soleus muscle fibers. The mRNA and protein expression of autophagy-related genes, such as Beclin-1, LC3B, Bnip3, p62 and Cathepsin L, were increased in the soleus muscle of GK rats fed with NPD compared to Wistar rats. Importantly, LPD resulted in a slight reduction in the expression of autophagy-related genes; however, these differences were not statistically significant. In addition, LPD+KA abolished the upregulation of autophagy-related gene expression. Furthermore, the activation of autophagy in the NPD and LPD groups was confirmed by the appearance of autophagosomes or autolysosomes using electron microscopy, when compared with the Control and LPD+KA groups. Our results showed that LPD+KA abolished the activation of autophagy in skeletal muscle and decreased muscle loss in rats with type 2 diabetic nephropathy.
Highlights
Type 2 diabetic nephropathy is the most common cause of endstage renal disease (ESRD)
Chronic kidney disease is associated with a loss in body protein mass and fuel reserves, which is known as protein-energy wasting (PEW)
We sought to determine the effect of a low-protein diet supplemented with ketoacids on muscle atrophy and autophagy in rats with type 2 diabetic nephropathy
Summary
Type 2 diabetic nephropathy is the most common cause of endstage renal disease (ESRD). The treatment strategies for renal failure, including the use of protein-restricted diets [1], have gained increased interest for the treatment of patients with diabetic nephropathy. A nitrogen-free ketoanalog, has been prescribed together with a low-protein diet in patients with CKD [9,10]. Results of a clinical trial have suggested that protein restriction supplemented with essential amino acids and ketoanalogs delays the onset of end-stage renal failure without deteriorating the nutritional status of patients with nondiabetic [12,13] or diabetic nephropathy [14,15].
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