Pentoxifylline attenuates proteinuria in anti-Thy1 glomerulonephritis via downregulation of nuclear factor-κB and Smad2/3 signaling
Journal
Molecular Medicine
Journal Volume
21
Pages
276-284
Date Issued
2015
Author(s)
Abstract
Anti-Thy1 glomerulonephritis is a rat nephritis model closely simulating human mesangial proliferative glomerulonephritis. It affects primarily the mesangium, yet displays substantial proteinuria during the course. This study investigated the molecular signals underlying proteinuria in this disease and the modulation of which by the known antiproteinuric agent, pentoxifylline. Male Wistar rats were randomly divided into a control group and nephritic groups with or without treatment with IMD-0354 (an IκB kinase inhibitor), SB431542 (an activin receptor–like kinase inhibitor) or pentoxifylline. Kidney sections were prepared for histological examinations. Glomeruli were isolated for mRNA and protein analysis. Urine samples were collected for protein and nephrin quantitation. One day after nephritis induction, proteinuria developed together with ultrastructural changes of the podocyte and downregulation of podocyte mRNA and protein expression. These were associated with upregulation of tumor necrosis factor (TNF)-α and transforming growth factor (TGF)-β/activins mRNAs and activation of nuclear factor (NF)-κB p65 and Smad2/3. IMD-0354 attenuated proteinuria on d 1, whereas SB431542 decreased proteinuria on d 3 and 5, in association with partial restoration of downregulated podocyte mRNA and protein expression. Pentoxifylline attenuated proteinuria and nephrinuria through the course, plus inhibition of p-NF-κB p65 (d 1) and p-Smad2/3 (d 5) and partial reversal of downregulated podocyte mRNA and protein. Our data show that the pathogenesis of proteinuria in anti-Thy1 glomerulonephritis involves TNF-α and TGF-β/activin pathways, and the evolution of this process can be attenuated by pentoxifylline via downregulation of NF-κB and Smad signals and restoration of the podocyte component of the glomerular filtration barrier. ? 2015, Uninversity of Michigan. All rights reserved.
SDGs
Other Subjects
4 [4 (1,3 benzodioxol 5 yl) 5 (2 pyridinyl) 1h imidazol 2 yl]benzamide; activin; activin A; alpha smooth muscle actin; CD2 associated protein; glipican 1; I kappa B kinase inhibitor; imd 0354; immunoglobulin enhancer binding protein; interleukin 1beta; membrane protein; messenger RNA; monoclonal antibody; monoclonal antibody Thy1; monocyte chemotactic protein 1; nephrin; pentoxifylline; placebo; podocin; Smad2 protein; Smad3 protein; synaptopodin; syndecan 4; transcription factor RelA; transforming growth factor beta1; transforming growth factor beta2; transforming growth factor beta3; tumor necrosis factor alpha; unclassified drug; WT1 protein; anaplastic lymphoma kinase; cytokine; immunoglobulin enhancer binding protein; pentoxifylline; protein tyrosine kinase; Smad2 protein; Smad3 protein; Thy 1 antigen; animal cell; animal experiment; animal model; animal tissue; Article; cellular distribution; controlled study; cytokine production; cytokine release; down regulation; drug efficacy; drug targeting; electron microscopy; gene expression regulation; glomerulus; glomerulus filtration; histopathology; male; nonhuman; pathogenesis; podocyte; priority journal; proliferative glomerulonephritis; protein analysis; protein degradation; protein expression; protein localization; protein urine level; proteinuria; rat; rat model; RNA gene; signal transduction; tissue distribution; transcription regulation; ultrastructure; urinalysis; animal; antagonists and inhibitors; complication; disease model; gene expression; genetics; glomerulonephritis; human; immunology; metabolism; proteinuria; Animals; Antigens, Thy-1; Cytokines; Disease Models, Animal; Gene Expression; Glomerulonephritis; Humans; Male; NF-kappa B; Pentoxifylline; Proteinuria; Rats; Receptor Protein-Tyrosine Kinases; Signal Transduction; Smad2 Protein; Smad3 Protein
Publisher
Uninversity of Michigan
Type
journal article