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Pentoxifylline Attenuates Proteinuria in Anti-Thy1 Glomerulonephritis via
Downregulation of Nuclear Factor-?B and Smad2/3 Signaling
#MMPMID25879629
Chen YM
; Chiang WC
; Yang Y
; Lai CF
; Wu KD
; Lin SL
Mol Med
2015[Apr]; 21
(1
): 276-84
PMID25879629
show ga
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 I?B 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)-? and transforming growth factor (TGF)-?/activins mRNAs and
activation of nuclear factor (NF)-?B 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-?B 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-? and
TGF-?/activin pathways, and the evolution of this process can be attenuated by
pentoxifylline via downregulation of NF-?B and Smad signals and restoration of
the podocyte component of the glomerular filtration barrier.
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