Faculty Collaboration Database

Serotonin 5-HT2A receptor induces TGF-beta1 expression in mesangial cells via ERK: proliferative and fibrotic signals. Am J Physiol 1999 Jun;276(6):F922-30

Date

06/11/1999

Pubmed ID

10362781

DOI

10.1152/ajprenal.1999.276.6.F922

Scopus ID

2-s2.0-0033143762 (requires institutional sign-in at Scopus site)   134 Citations

Abstract

We examined the links between fibrotic and proliferative pathways for the 5-HT2A receptor in rat mesangial cells. Serotonin (5-hydroxytryptamine, 5-HT) induced transforming growth factor-beta1 (TGF-beta1) mRNA in a concentration-dependent (peak at 30 nM 5-HT) and time-dependent fashion. For 10 nM 5-HT, the effect was noticeable at 1 h and maximal by 6 h. Inhibition of 1) protein kinase C (PKC), 2) mitogen- and extracellular signal-regulated kinase kinase (MEK1) with 2'-amino-3'-methoxyflavone (PD-90859), and 3) extracellular signal-regulated kinase (ERK) with apigenin attenuated this effect. The effect was blocked by antioxidants, N-acetyl-L-cysteine (NAC) and alpha-lipoic acid, and mimicked by direct application of H2O2. TGF-beta1 mRNA induction was also blocked by diphenyleneiodonium and 4-(2-aminoethyl)-benzenesulfonyl fluoride, which inhibit NAD(P)H oxidase, a source of oxidants. 5-HT increased the amount of TGF-beta1 protein, validating the mRNA studies and demonstrating that 5-HT potently activates ERK and induces TGF-beta1 mRNA and protein in mesangial cells. Mapping studies strongly supported relative positions of the components of the signaling cascade as follow: 5-HT2A receptor --> PKC --> NAD(P)H oxidase/reactive oxygen species --> MEK --> ERK --> TGF-beta1 mRNA. These studies demonstrate that mitogenic signaling components (PKC, MEK, and oxidants) are directly linked to the regulation of TGF-beta1, a key mediator of fibrosis. Thus a single stimulus can direct both proliferative and fibrotic signals in renal mesangial cells.

Author List

Grewal JS, Mukhin YV, Garnovskaya MN, Raymond JR, Greene EL

Author

John R. Raymond MD President, CEO, Professor in the President department at Medical College of Wisconsin

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

Animals
Calcium-Calmodulin-Dependent Protein Kinases
Cell Division
Fibrosis
GTP-Binding Proteins
Glomerular Mesangium
MAP Kinase Kinase 1
Male
Mitogen-Activated Protein Kinase Kinases
NADPH Oxidases
Protein Kinase C
Protein-Tyrosine Kinases
RNA, Messenger
Rats
Rats, Sprague-Dawley
Reactive Oxygen Species
Receptors, Serotonin
Signal Transduction
Transforming Growth Factor beta
Virulence Factors, Bordetella