1,721,037 research outputs found
Serum Amyloid P Inhibits Fibrosis through Fc Gamma R-Dependent Monocyte- Macrophage Regulation in Vivo (Vol 1, 5ra13, 2009)
No full textPentoxifylline Inhibits Platelet-Derived Growth Factor-Stimulated Cyclin D1 Expression in Mesangial Cells by Blocking Akt Membrane Translocation
No full textPentoxifylline (PTX) is a potent inhibitor of mesangial cell pro-liferation,
but its underlying mechanism is poorly understood.
Here, we demonstrate that in platelet-derived growth factor
(PDGF)-stimulated mesangial cells, PTX causes G1 arrest by
down-regulation of cyclin D1 expression, which subsequently
attenuates Cdk4 activity. In vivo, PTX similarly reduces cyclin
D1 expression in mesangial cells of rats with acute Thy1 glo-merulonephritis.
The mechanism by which PTX reduces cyclin
D1 is also investigated. PTX blocks Akt but not phosphatidyl-inositol
3-kinase (PI3K) activation in response to PDGF and
abrogates cyclin D1 induction by PI3K, suggesting an effect of
PTX on Akt itself. Indeed, PTX is capable of blocking the
membrane translocation of Akt, and enforced targeting of Akt
to cell membrane prevents the inhibition of Akt and cyclin D1 by
PTX. Because PTX is known to increase intracellular cAMP
levels by inhibiting phosphodiesterase, the role of protein ki-nase
A (PKA) in these events is investigated. The PKA antago-nist
N-[2-(4-bromocinnamylamino)ethyl]-5-isoquinoline (H89)
abolishes cell proliferation effects of PTX and restores cyclin D1
expression as well as Akt membrane translocation and activa-tion
by PDGF, whereas dibutyryl cAMP and forskolin recapitu-late
the functions of PTX in mesangial cells. In conclusion, our
results indicate that PTX, acting through PKA, interferes with
PDGF signaling to Akt activation by blocking Akt membrane
translocation, thereby inhibiting cyclin D1 expression and mes-angial
cell proliferation
Effect of Pentoxifylline in Addition to Losartan on Proteinuria and GFR in CKD：A 12-month Randomized Trial
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Pericytes and Perivascular Fibroblasts Are the Primary Source of Collagen- Producing Cells in Obstructive Fibrosis of the Kidney
No full textUnderstanding the origin of scar-producing myofibroblasts is vital in discerning the mechanisms by which fibrosis develops in response to inflammatory injury. Using a transgenic reporter mouse model expressing enhanced green fluorescent protein (GFP) under the regulation of the collagen type I, 1 (coll1a1) promoter and enhancers, we examined the origins of coll1a1-producing cells in the kidney. Here we show that in normal kidney, both podocytes and pericytes generate coll1a1 transcripts as detected by enhanced GFP, and that in fibrotic kidney, coll1a1-GFP expression accurately identifies myofibroblasts. To determine the contribution of circulating immune cells directly to scar production, wild -type mice, chimeric with bone marrow from coll-GFP mice, underwent ureteral obstruction to induce fibrosis. Histological examination of kidneys from these mice showed recruitment of small numbers of fibrocytes to the fibrotic kidney, but these fibrocytes made no significant contribution to interstitial fibrosis. Instead, using kinetic modeling and time course microscopy, we identified coll1a1-GFP-expressing pericytes as the major source of interstitial myofibroblasts in the fibrotic kidney . Our studies suggest that either vascular injury or vascular factors are the most likely triggers for pericyte migration and differentiation into myofibroblasts. Therefore , our results serve to refocus fibrosis research to injury of the vasculature rather than injury to the epithelium
Outcomes of Stage 3-5 Chronic Kidney Disease before End-Stage Renal Disease at a Single Center in Taiwan
No full textPentoxifylline Inhibits Platelet-Derived Growth Factor-Stimulated Cyclin D1 Expression in Mesangial Cells by Blocking Akt Membrane Translocation
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The role played by perivascular cells in kidney interstitial injury
No full textFibrosis of the kidney is a disease affecting millions worldwide and is a harbinger of progressive loss of organ function resulting in organ failure. Recent findings suggest that understanding mechanisms of development and progression of fibrosis will lead to new therapies urgently required to counteract loss of organ function. Recently, little-known cells that line the kidney microvasculature, known as pericytes, were identified as the precursor cells which become the scar-forming myofibroblasts. Kidney pericytes are extensively branched cells located in the wall of capillaries, embedded within the microvascular basement membrane, and incompletely envelope endothelial cells with which they establish focal contacts. In response to kidney injuries, pericytes detach from endothelial cells and migrate into the interstitial space where they undergo a transition into myofibroblasts. Detachment leads to fibrosis but also leaves an unstable endothelium, prone to rarefaction. Endothelial-pericyte crosstalk at the vascular endothelial growth factor receptors and platelet derived growth factor receptors in response to injury have been identified as major new targets for therapeutic intervention
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