Rapamycin Ameliorates Proteinuria-Associated Tubulointerstitial Inflammation and Fibrosis in Experimental Membranous Nephropathy

Bonegio, Ramon; Fuhro, Robert; Wang, Zhiyong; Valeri, C. R.; Andry, Chris; Salant, David J.; Lieberthal, Wilfred

doi:10.1681/asn.2004030180

Cited by 150 publications

(112 citation statements)

References 46 publications

Supporting

Mentioning

100

Contrasting

Unclassified

Order By: Relevance

“…The beneficial effects of mTOR inhibition have recently been reported in several rat models of chronic kidney disease, i.e., hypertensive 5 ⁄6 nephrectomy, diabetic nephropathy, hypertrophy following unilateral nephrectomy, tubulointerstitial fibrosis due to urethral obstruction or nephrotic syndrome, and polycystic kidney disease (2,5,10,19,26,29). These beneficial results are now expanded toward a progressive model of human mesangioproliferative nephropathy as a leading cause of end-stage kidney disease worldwide (13,14).…”

Section: Discussionmentioning

confidence: 98%

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

Krämer

Wang-Rosenke²,

Scholl³

et al. 2008

American Journal of Physiology-Renal Physiology

View full text Add to dashboard Cite

-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

show abstract

Section: Discussionmentioning

confidence: 98%

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

Krämer

Wang-Rosenke²,

Scholl³

et al. 2008

American Journal of Physiology-Renal Physiology

View full text Add to dashboard Cite

show abstract

“…After Masson's trichrome staining, the degree of tubulointerstitial fibrosis was assessed by a point-counting method as described previously. 16 Briefly, a standardized grid of 70 points was superimposed on the microscope, and the number of points over the glomeruli, tubular epithelium, and interstitial tissue were counted and scored as 0 for 0%, 1 for o25%, 2 for 25-50%, 3 for 51-75%, and 4 for 475% for each field with tubulointerstitial fibrosis. Macrophage infiltration was detected by rat anti-mouse F4/80 antibody (1:2000; Serotec, Raleigh, NC, USA) and incubated at room temperature for 1 h, followed by use of the Envision kit (Dako, Carpinteria, CA, USA).…”

Section: Light Microscopy and Immunohistochemistrymentioning

confidence: 99%

Dipeptidyl peptidase IV inhibitor protects against renal interstitial fibrosis in a mouse model of ureteral obstruction

Min

Kim

et al. 2014

Laboratory Investigation

View full text Add to dashboard Cite

Dipeptidyl peptidase IV (DPPIV) is an exopeptidase that modulates the function of several substrates, among which insulin-releasing incretin hormones are the most well known. DPPIV also modulate substrates involved in inflammation, cell migration, and cell differentiation. Although DPPIV is highly expressed in proximal renal tubular cells, the role of DPPIV inhibition in renal disease is not fully understood. For this reason, we investigated the effects of LC15-0444, a DPPIV inhibitor, on renal function in a mouse model of renal fibrosis. Eight-week-old C57/BL6 mice were subjected to unilateral ureteral obstruction (UUO) and were treated with LC15-0444 (a DPPIV inhibitor) at a dose of 150 mg/kg per day in food or vehicle for 14 days. DPPIV activity was significantly increased in obstructed kidneys, and reduced after treatment with LC15-0444. Administration of LC15-0444 resulted in a significant decrease in albuminuria, urinary excretion of 8-isoprostane, and renal fibrosis. DPPIV inhibition also substantially decreased the synthesis of several proinflammatory and profibrotic molecules, as well as the infiltration of macrophages. UUO significantly increased, and LC15-0444 markedly suppressed, levels of phosphorylated Smad2/3, TGFb1, toll-like receptor 4, high-mobility group box-1, NADPH oxidase 4, and NF-kB. These results suggest that activation of DPPIV in the kidney has a role in the progression of renal disease and that targeted therapy inhibiting DPPIV may prove to be a useful new approach in the management of progressive renal disease, independent of mechanisms mediated by glucagon-like peptide-1.

show abstract

“…Increased mTOR activity has been reported in different glomerular diseases, and mTORC1 inhibition by rapamycin and everolimus shows beneficial effects against diabetic nephropathy, focal segmental glomerulosclerosis, minimal change disease, membranous nephropathy, etc. (7)(8)(9)(10). But contrasting evidence also indicates that mTORC1 inhibition by the immunosuppressive drug rapamycin leads proteinuria and podocyte apoptosis and develops primary focal segmental glomerulosclerosis in renal transplant recipients (11).…”

mentioning

confidence: 99%

Transforming Growth Factor β1-induced Apoptosis in Podocytes via the Extracellular Signal-regulated Kinase-Mammalian Target of Rapamycin Complex 1-NADPH Oxidase 4 Axis

Das

Nguyen

et al. 2015

Journal of Biological Chemistry

View full text Add to dashboard Cite

TGF-␤ is a pleiotropic cytokine that accumulates during kidney injuries, resulting in various renal diseases. We have reported previously that TGF-␤1 induces the selective up-regulation of mitochondrial Nox4, playing critical roles in podocyte apoptosis. Here we investigated the regulatory mechanism of Nox4 up-regulation by mTORC1 activation on TGF-␤1-induced apoptosis in immortalized podocytes. TGF-␤1 treatment markedly increased the phosphorylation of mammalian target of rapamycin (mTOR) and its downstream targets p70S6K and 4EBP1. Blocking TGF-␤ receptor I with SB431542 completely blunted the phosphorylation of mTOR, p70S6K, and 4EBP1. Transient adenoviral overexpression of mTOR-WT and constitutively active mTOR⌬ augmented TGF-␤1-treated Nox4 expression, reactive oxygen species (ROS) generation, and apoptosis, whereas mTOR kinase-dead suppressed the above changes. In addition, knockdown of mTOR mimicked the effect of mTOR-KD. Inhibition of mTORC1 by low-dose rapamycin or knockdown of p70S6K protected podocytes through attenuation of Nox4 expression and subsequent oxidative stress-induced apoptosis by TGF-␤1. Pharmacological inhibition of the MEK-ERK cascade, but not the PI3K-Akt-TSC2 pathway, abolished TGF-␤1-induced mTOR activation. Inhibition of either ERK1/2 or mTORC1 did not reduce the TGF-␤1-stimulated increase in Nox4 mRNA level but significantly inhibited total Nox4 expression, ROS generation, and apoptosis induced by TGF-␤1. Moreover, double knockdown of Smad2 and 3 or only Smad4 completely suppressed TGF-␤1-induced ERK1/2-mTOR activation. Our data suggest that TGF-␤1 increases translation ofNox4throughtheSmad-ERK1/2-mTORC1axis,whichisindependent of transcriptional regulation. Activation of this pathway plays a crucial role in ROS generation and mitochondrial dysfunction, leading to podocyte apoptosis. Therefore, inhibition of the ERK1/2-mTORC1 pathway could be a potential therapeutic and preventive target in proteinuric and chronic kidney diseases.Podocyte damage is one of the key determinants of the majority of diabetic and non-diabetic glomerular diseases, leading to chronic kidney diseases and end-stage renal disease (1). Leakage of plasma proteins in the urine indicates the onset of renal diseases that are associated with podocyte injury (2-4). Recent evidence has shown that mammalian target of rapamycin (mTOR) 3 signaling activation is an important mediator of diabetic nephropathy in mice and humans (5, 6). Increased mTOR activity has been reported in different glomerular diseases, and mTORC1 inhibition by rapamycin and everolimus shows beneficial effects against diabetic nephropathy, focal segmental glomerulosclerosis, minimal change disease, membranous nephropathy, etc. (7-10). But contrasting evidence also indicates that mTORC1 inhibition by the immunosuppressive drug rapamycin leads proteinuria and podocyte apoptosis and develops primary focal segmental glomerulosclerosis in renal transplant recipients (11). Therefore, it might be important to investigate the detailed molecular mechanisms to...

show abstract

Rapamycin Ameliorates Proteinuria-Associated Tubulointerstitial Inflammation and Fibrosis in Experimental Membranous Nephropathy

Cited by 150 publications

References 46 publications

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

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

Dipeptidyl peptidase IV inhibitor protects against renal interstitial fibrosis in a mouse model of ureteral obstruction

Transforming Growth Factor β1-induced Apoptosis in Podocytes via the Extracellular Signal-regulated Kinase-Mammalian Target of Rapamycin Complex 1-NADPH Oxidase 4 Axis

Contact Info

Product

Resources

About