PGE1 inhibits the expression of PAI-1 mRNA induced by TNF-alpha in human mesangial cells.
We examined the effect of PGE1 on the expression of plasminogen activator inhibitor-1 (PAI-1) mRNA induced by tumor necrosis factor-alpha (TNF-alpha) in human mesangial cells, because PAI-1 is one of major factors for the progression of glomerulosclerosis. The expression of PAI-1 mRNA was increased after stimulation with TNF-alpha, and it was diminished by pre-incubation with PGE1. Next, we examined the effect of PGE1 on the phosphorylation of mitogen activated protein kinase (MAPK) family and Akt. TNF-alpha activated the phosphorylation of p44/42 MAPK, p38 MAPK, SAPK/JNK and Akt in mesangial cells. PGE1 inhibited the TNF-alpha induced phosphorylation of SAPK/JNK and Akt, but not p44/42 MAPK and p38 MAPK. The TNF-alpha induced expression of PAI-1 mRNA was not affected by PD98059, an inhibitor of MEK, SB203580, an inhibitor of p38 MAPK, nor LY294002, an inhibitor of PI3 K. However, DMAP, an inhibitor of SAPK/JNK, inhibited the expression of PAI-1 mRNA, suggesting that the TNF-alpha induced expression of PAI-1 mRNA is regulated by the SAPK/JNK dependent pathway in human mesangial cells. By the incubation with H8, an inhibitor of PKA, the inhibitory effect of PGE1 on the expression of PAI-1 mRNA was abolished, suggesting that PGE1 inhibited the PAI-1 mRNA expression via the PKA pathway. Our results suggest that the inhibition of PAI-1 synthesis by PGE1 in human mesangial cells may have therapeutic implications for glomerulosclerosis such as occurs in diabetic nephropathy.
Kishida
M
M
Toyama Medical and Pharmaceutical University, Faculty of Medicine, the First Department of Internal Medicine, 2630 Sugitani, Toyama-shi, Toyama 930-0192, Japan.
Urakaze
M
M
Takata
M
M
Nobata
Y
Y
Yamamoto
N
N
Temaru
R
R
Sato
A
A
Yamazaki
K
K
Nakamura
N
N
Kobayashi
M
M
D000527:Alprostadil / Q000494:pharmacology*; D015152:Blotting, Northern; D015153:Blotting, Western; D000242:Cyclic AMP / Q000378:metabolism; D003928:Diabetic Nephropathies / Q000276:immunology*; D004347:Drug Interactions; D005920:Glomerular Mesangium / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D010766:Phosphorylation; D017395:Plasminogen Activator Inhibitor 1 / Q000096:biosynthesis* / Q000235:genetics; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000494:pharmacology*
D017395:Plasminogen Activator Inhibitor 1; D047428:Protein Kinase Inhibitors; D014409:Tumor Necrosis Factor-alpha; D000242:Cyclic AMP; D020928:Mitogen-Activated Protein Kinases; D000527:Alprostadil