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

Abstract

-dose mTOR inhibition by rapamycin attenuates progression in anti-thy1-induced chronic glomerulosclerosis of the rat. Am J Physiol Renal Physiol 294: F440-F449, 2008. First published December 19, 2007 doi:10.1152/ajprenal.00379.2007.-Treatment options in human mesangioproliferative glomerulonephritis/sclerosis, mostly IgA nephropathy, are limited. Progressive mesangioproliferative nephropathy represents a major cause of end-stage kidney disease. The present study explores the efficacy of low-dose mTOR inhibition by rapamycin in a chronic-progressive model of mesangioproliferative glomerulosclerosis (cGS). cGS was induced by high-dose anti-thy1 antibody injection into uninephrectomized rats. Rapamycin administration (2.5 mg ⅐ kg Ϫ1 ⅐ body wt Ϫ1 ) was started 10 days after antibody injection and continued until week 20. cGS was characterized by advancing proteinuria, increased blood pressure, marked tubulointerstitial and glomerular fibrosis, cell proliferation and round cell infiltration, and impaired renal function. KruskalWallis and Mann-Whitney U-tests were used for statistical analysis. The course of chronic anti-thy1-induced glomerulosclerosis was significantly attenuated by low-dose rapamycin treatment. In week 20, this was demonstrated by improvements in proteinuria (Ϫ38%), systolic blood pressure (Ϫ16 mmHg), tubulointerstitial and glomerular histological matrix accumulation (Ϫ61 and Ϫ24%), transforming growth factor-␤1 overexpression (Ϫ41 and Ϫ47%), collagen I deposition (Ϫ53 and Ϫ65%), cell proliferation (Ϫ90 and Ϫ76%), and leukocyte number (macrophages Ϫ52 and Ϫ53%; lymphocytes Ϫ58 and 51%), respectively. Rapamycin improved renal function as well (blood creatinine Ϫ0.68 mg/dl, urea Ϫ66.7 mg/day, and creatinine clearance ϩ0.13 ml ⅐ min Ϫ1

The Role of the Mammalian Target Of Rapamycin (mTOR) in Renal Disease

“…84 Similar findings were reported in animal models of CKD from other causes, including reduced renal mass from five-sixths nephrectomy, 82 renal obstruction after ureteral ligation, 81,85 and chronic mesangioproliferative glomerulonephritis induced by antiThy1 antibody. 73,86 In summary, mTOR plays an important role in the progression of CKD in a variety of animal models. Available evidence suggests a hypothetical schema to explain the beneficial effects of rapamycin on the progression of CKD ( Figure 3).…”

Artesunate modulates expression of matrix metalloproteinases and their inhibitors as well as collagen-IV to attenuate pulmonary fibrosis in rats

“…Artesunate treatment resulted in decreased collagen-IV protein in lung tissues and decreased collagen-IV mRNA in primary lung fibroblast cells, indicating that the anti-fibrotic effect of artesunate might be involve, at least partially, downregulation collagen-IV expression. MMP-2 and MMP-9 are well-known owing to their ability to degrade collagen-IV, and their increased activity leads to various pulmonary diseases including pulmonary fibrosis (Krämer et al, 2008;Bridle et al, 2009;Korfhagen et al, 2009). MMP-2 and MMP-9 play an important role in the inefficient remodeling of damaged lung tissue (Checa et al, 2008;Yamashita et al, 2011;Song et al, 2013).…”

Effect of mesenchymal stem cells on anti-Thy1,1 induced kidney injury in albino rats

“…In this work, an increase in expression of α-SMA was recorded in kidney of rats injected with anti-Thy1. α-SMA expression is a typical molecular marker of myofibroblasts in many nephropathies [1] . In agreement with the present result, Abbate et al reported that the development of fibrosis in anti-Thy1 treated rat is paralleled by increased expression of α-SMA in the tubulo-interstitial area due to peritubular accumulation of myofibroblasts [24] .…”

“…It is used as standard animal model to produce experimental glomerulonephritis which is popularly known in the field of nephrology as anti-Thy1 glomerulonephritis. Glomerulonephritis induced by a single injection of antiThy1 antibody is characterized by an acute and selfresolving disease process, whereas repeated injection of the antibody induces irreversible glomerulosclerosis [1] . Masuda et al studied the pathological process of glomerulonephritis including glomerular capillary damage, and vascular endothelial growth factor (VEGF) after anti-Thy1,1 treatment in rats [2] .…”