Attenuation of the activated mammalian target of rapamycin pathway might be associated with renal function reserve by a low-protein diet in the rat remnant kidney model

Abstract

The mammalian target of rapamycin (mTOR), a regulator of cellular protein synthesis and cell growth, plays an important role in the progression of renal hypertrophy and renal dysfunction in experimental chronic kidney disease models. Because the mTOR activity is regulated by nutrients including amino acids, we tested the hypothesis that the renoprotective effect of a low-protein diet (LPD) might be associated with the attenuation of the renal mTOR pathway. In this study, 5/6 nephrectomized rats were fed an LPD or a normal protein diet (NPD), and a number of rats that were fed an NPD received rapamycin (1.0 mg kg⁻¹ d⁻¹), a specific inhibitor of mTOR. After 6 weeks, renal tissue was collected to evaluate the activity of the mTOR pathway and histologic changes. The phosphorylation of p70S6k, a kinase in the downstream of mTOR, was significantly higher in the NPD-fed rats that showed progressive renal dysfunction than in the sham-operated rats (NPD). The LPD attenuated the excessive phosphorylation of p70S6k concomitant with reduced proteinuria and improved renal histologic changes in the 5/6 nephrectomized rats. The effects of the LPD were similar to the effects of rapamycin. The expression of phosphorylated p70S6k was significantly correlated with proteinuria (r² = 0.63, P < .001), the glomerular area (r² = 0.60, P < .001), and the number of phosphorylated Smad2-positive cells in the glomerulus (r² = 0.26, P < .05) of these rats. These results suggest that the preventive effect of an LPD on the progression of renal failure is associated with attenuation of the activated mTOR/p70S6k pathway in the rat remnant kidney model.

Keywords: CKD; ECM; HIF; Low-protein diet; Nx-LPD; Nx-NPD; Nx-RAP; PBS; PCNA; Rat; Remnant kidney; Renal function; TGF-β; chronic kidney diseases; extracellular matrix protein; hypoxia-inducible factor; mTOR; mammalian target of rapamycin; nephrectomized rats fed with a low-protein diet; nephrectomized rats fed with a normal protein diet; nephrectomized rats fed with a normal protein diet and rapamycin; phosphate-buffered saline; proliferative cell nuclear antigen; transforming growth factor β; α-SMA; α-smooth muscle actin.