Faculty Collaboration Database

PreproEndothelin-1 expression in human mesangial cells: evidence for a p38 mitogen-activated protein kinase/protein kinases-C-dependent mechanism. J Am Soc Nephrol 2001 Jun;12(6):1137-1150

Date

05/25/2001

Pubmed ID

11373337

DOI

10.1681/ASN.V1261137

Scopus ID

2-s2.0-0035005504 (requires institutional sign-in at Scopus site)   20 Citations

Abstract

Endothelin-1 (ET-1) has been implicated in the pathogenesis of renal inflammation. This study investigated the mechanisms underlying the synergistic upregulation of preproET-1 gene expression in human mesangial cells after co-stimulation with thrombin and tumor necrosis factor alpha (TNFalpha). Whereas thrombin induced a moderate upregulation of preproET-1 mRNA, co-stimulation with TNFalpha resulted in a strong and protracted upregulation of this mRNA species. Thrombin+TNFalpha-induced upregulation of preproET-1 expression was found to require p38 mitogen-activated protein kinase and protein kinases C, whereas activation of extracellular signal-regulated kinase, c-Jun-N-terminal kinase, or intracellular Ca(2+) release were not required. Actinomycin D chase experiments suggested that enhanced stability of preproET-1 mRNA did not account for the increase in transcript levels. PreproET-1 promoter analysis demonstrated that the 5'-flanking region of preproET-1 encompassed positive regulatory elements engaged by thrombin. Negative modulation of thrombin-induced activation exerted by the distal 5' portion of preproET-1 promoter (-4.4 kbp to 204 bp) was overcome by co-stimulation with TNFalpha, providing a possible mechanism underlying the synergistic upregulation of preproET-1 expression by these two agonists. In conclusion, human mesangial cell expression of preproET-1 may be increased potently in the presence of two common proinflammatory mediators, thereby providing a potential mechanism for ET-1 production in inflammatory renal disease.

Author List

Foschi M, Sorokin A, Pratt P, McGinty A, Villa G, Franchi F, Dunn MJ

Author

Andrey Sorokin PhD Professor in the Medicine department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Blotting, Northern
Calcium
Cells, Cultured
Chloramphenicol O-Acetyltransferase
Endothelins
Endothelium, Vascular
Female
Gene Expression Regulation
Genetic Vectors
Glomerular Mesangium
Humans
Male
Mitogen-Activated Protein Kinase 11
Mitogen-Activated Protein Kinases
Protein Kinase C
Protein-Tyrosine Kinases
RNA, Messenger
Rats
Rats, Sprague-Dawley
Thrombin
Transfection
Tumor Necrosis Factor-alpha
Up-Regulation