title: 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.
authors.affiliation: Department of Clinical Nutrition, School of Food and Nutritional Sciences, University of Shizuoka, Shizuoka 422-8526, Japan. Electronic address: ohkawa@u-shizuoka-ken.ac.jp.
authors.forename: Sakae
authors.initials: S
authors.lastname: Ohkawa
authors.forename: Momoko
authors.initials: M
authors.lastname: Yanagida
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Uchikawa
authors.forename: Takuya
authors.initials: T
authors.lastname: Yoshida
authors.forename: Naoki
authors.initials: N
authors.lastname: Ikegaya
authors.forename: Hiromichi
authors.initials: H
authors.lastname: Kumagai
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D018753:Diet, Protein-Restricted; D004044:Dietary Proteins / Q000008:administration & dosage; D004195:Disease Models, Animal; D006984:Hypertrophy / Q000473:pathology; D007668:Kidney / Q000187:drug effects* / Q000473:pathology; D008297:Male; D010766:Phosphorylation; D011507:Proteinuria / Q000178:diet therapy; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D020123:Sirolimus / Q000008:administration & dosage; D051899:Smad2 Protein / Q000235:genetics / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism
chemical_list: D004044:Dietary Proteins; D051899:Smad2 Protein; C497784:Smad2 protein, rat; C546845:mTOR protein, rat; D051057:Proto-Oncogene Proteins c-akt; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus
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