Inhibition of mTOR signaling with rapamycin attenuates renal hypertrophy in the early diabetic mice

• Published in: Biochemical and biophysical research communications 2006-02, Vol.340 (1), p.296-301
• Main Authors: Sakaguchi, Masayoshi, Isono, Motohide, Isshiki, Keiji, Sugimoto, Toshiro, Koya, Daisuke, Kashiwagi, Atsunori
• Format: Article
• Language: English
• Subjects: Animals; Diabetes Mellitus, Experimental - chemically induced; Diabetes Mellitus, Experimental - complications; Diabetes Mellitus, Experimental - drug therapy; Diabetes Mellitus, Experimental - metabolism; Diabetes Mellitus, Experimental - pathology; Diabetic Nephropathies - chemically induced; Diabetic Nephropathies - drug therapy; Diabetic Nephropathies - metabolism; Diabetic Nephropathies - pathology; Diabetic nephropathy; Disease Progression; Hypertrophy - drug therapy; Hypertrophy - metabolism; Hypertrophy - pathology; Immunosuppressive Agents - administration & dosage; Injections, Intraperitoneal; Kidney - drug effects; Kidney - metabolism; Kidney - pathology; Male; Mammalian target of rapamycin; Mice; Mice, Inbred C57BL; Organ Size - drug effects; Protein Kinases - metabolism; Rapamycin; Renal hypertrophy; Severity of Illness Index; Signal Transduction - drug effects; Sirolimus - administration & dosage; Streptozocin; TOR Serine-Threonine Kinases; Treatment Outcome
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2005.12.012

Early diabetic nephropathy is characterized by renal hypertrophy that is mainly due to proximal tubular hypertrophy. Mammalian target of rapamycin (mTOR) is a serine/threonine protein kinase, and its signaling has been reported to regulate protein synthesis and cellular growth, specifically, hypertrophy. Therefore, we examined the effect of mTOR signaling on diabetic renal hypertrophy by using the specific inhibitor for mTOR, rapamycin. Ten days after streptozotocin-induced diabetes, mice showed kidney hypertrophy with increases in the phosphorylation of p70S6kinase and the expression of cyclin kinase inhibitors, p21 Cip1 and p27 Kip1, in the kidneys. The intraperitoneal injection of rapamycin (2 mg/kg/day) markedly attenuated the enhanced phosphorylation of p70S6kinase, the increment of cyclin-dependent kinase inhibitors, and renal enlargement without any changes of clinical parameters, including blood glucose, blood pressure, and food intake. Overexpression of a constitutive active form of p70S6kinase resulted in increased cell size of cultured mouse proximal tubule cells; thus, activation of p70S6kinase causes hypertrophy of proximal tubular cells. Our findings suggest that activation of mTOR signaling causes renal hypertrophy at the early stage of diabetes.