Rapamycin Prevents Early Steps of the Development of Diabetic Nephropathy in Rats

Abstract

Background/Aims: Recent studies suggested the involvement of the Akt/mammalian target of rapamycin (mTOR) pathway in the pathogenesis of diabetic nephropathy. The effect of mTOR blockade by rapamycin in diabetic nephropathy was investigated, but in vivo study of rapamycin treatment in the course of early diabetes is still insufficient. This study was designed to determine the therapeutic effects of rapamycin on diabetic nephropathy at an early stage. Methods: Diabetes was induced in Sprague-Dawley rats with streptozotocin, and rapamycin (1 mg/kg) was administered by daily gavage for 4 weeks. Renal structural changes and some factors involved in the early pathogenesis of diabetic nephropathy were tested. The activation level of the Akt/mTOR pathway was also determined. Results: Rapamycin treatment reduced albuminuria, glomerular enlargement, glomerular basement membrane thickening, renal macrophage recruitment, and levels of renal mRNA expression of proliferating cell nuclear antigen, transforming growth factor-β₁, vascular endothelial growth factor, and monocyte chemoattractant protein-1 without change in blood glucose level and blood pressure in experimental diabetic rats. In addition, treatment with rapamycin also down-regulated the enhanced levels of renal p-Akt, phospho-p70S6 kinase, and phospho-ribosomal S6 protein in diabetic rats. Conclusions: Rapamycin treatment can prevent the early renal structural changes of diabetes in experimental rats, and thus halt the early steps of the development of diabetic nephropathy. mTOR blockade might be beneficial for the treatment of diabetic nephropathy.

A GSK-3/TSC2/mTOR pathway regulates glucose uptake and GLUT1 glucose transporter expression

“…However, there are hints that this regulatory pathway could be active in a less homeostatic relationship. Both enhanced mTOR activity (38,44) and increased GLUT1 expression (15) have been implicated in the pathogenesis of diabetic complications, especially nephropathy. Since upregulation of mTOR leads to enhanced GLUT1 expression, it is possible that mTOR plays a pathogenic role by stimulating GLUT1 expression and glucose uptake into susceptible glomerular cells in the kidney.…”

Low-dose mTOR inhibition by rapamycin attenuates progression in anti-thy1-induced chronic glomerulosclerosis of the rat

“…This may have contributed to the renoprotection observed with rapamycin treatment. With regard to their primary mode of pharmacological action (10,30), mTOR inhibitors pose no direct effect on blood pressure. Therefore, it is likely that the lower blood pressure with rapamycin in this study was mediated indirectly through less renal damage and fibrosis.…”

Plasma lipidomics reveal profound perturbation of glycerophospholipids, fatty acids, and sphingolipids in diet-induced hyperlipidemia

“…Increased ceramide(d18:0/16:0), ceramide monohexoside(d18:1/15:0), SM(d16:1/18:0), and SM(d18:1/18:0) were reversed by rapamycin. The previous study showed that ceramide increase in diabetic kidney and decrease after rapamycin treatment and the long established relationship of ceramide and apoptosis support ceramide as a reasonable biomarker candidate [141]. Streptozotocin significantly increased synthesis of many sphingolipids that was inhibited by rapamycin.…”