Angiotensin II activates plasminogen activator inhibitor-I promoter in renal tubular epithelial cells via the AT1 receptor.
BACKGROUND
Plasminogen activator inhibitor-1 (PAI-1) regulates normal extracellular matrix (ECM) metabolism and it is a key regulator of the fibrotic process. Both angiotensin II (Ang II) and angiotensin IV (Ang IV) have been reported to stimulate PAI-1 expression. It is not known how PAI-1 expression is regulated by the renin-angiotensin system (RAS) in renal tubular cells.


METHODS
To dissect signaling mechanisms contributing to the up-regulation of the PAI-1 promoter, porcine proximal tubular cells stably expressing the rabbit AT1 receptor (LLC-PK/AT1) were transiently transfected with a luciferase reporter construct containing the PAI-1 promoter. Promoter activation was assessed by measuring luciferase activity from cell lysates.


RESULTS
Ang II dose-dependently stimulated the transcriptional activity of the PAI-1 promoter in renal proximal tubular cells whereas Ang IV had no consistent effect on the promoter activity. Neither inhibition of the Extracellular Signal Regulated Kinase (ERK) cascade nor inhibition of the c-Jun-N-terminal Kinase (JNK) pathway did reduce the stimulation of the PAI-1 promoter by Ang II. However, genistein, a tyrosine kinase inhibitor blocked the effect of Ang II.


CONCLUSIONS
Ang II but not Ang IV activates the PAI-1 promoter in renal proximal tubular cells and this effect is mediated by tyrosine kinases.
Fintha
A
A
Nephrology Research Group, Hungarian Academy of Sciences and Semmelweis University, Budapest, Hungary.
Sebe
A
A
Masszi
A
A
Terebessy
T
T
Huszár
T
T
Rosivall
L
L
Mucsi
I
I
D000804:Angiotensin II / Q000031:analogs & derivatives / Q000494:pharmacology / Q000502:physiology*; D000818:Animals; D002478:Cells, Cultured; D004847:Epithelial Cells / Q000187:drug effects / Q000502:physiology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology; D019833:Genistein / Q000494:pharmacology; D048031:JNK Mitogen-Activated Protein Kinases / Q000502:physiology; D007687:Kidney Tubules, Proximal / Q000166:cytology*; D017395:Plasminogen Activator Inhibitor 1 / Q000096:biosynthesis*; D011401:Promoter Regions, Genetic / Q000187:drug effects; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D011817:Rabbits; D044140:Receptor, Angiotensin, Type 1 / Q000096:biosynthesis / Q000502:physiology*; D034421:Sus scrofa; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000502:physiology
D017395:Plasminogen Activator Inhibitor 1; D044140:Receptor, Angiotensin, Type 1; D016212:Transforming Growth Factor beta; D000804:Angiotensin II; C012877:angiotensin II, des-Asp(1)-des-Arg(2)-Ile(5)-; D019833:Genistein; D011505:Protein-Tyrosine Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases