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. doi: 10.1152/ajprenal.1999.276.6.F922.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Calcium-Calmodulin-Dependent Protein Kinases / physiology*
  • Cell Division / physiology
  • Fibrosis
  • GTP-Binding Proteins / drug effects
  • GTP-Binding Proteins / physiology
  • Glomerular Mesangium / cytology
  • Glomerular Mesangium / metabolism*
  • MAP Kinase Kinase 1
  • Male
  • Mitogen-Activated Protein Kinase Kinases*
  • NADPH Oxidases / metabolism
  • Protein Kinase C / physiology
  • Protein Serine-Threonine Kinases / physiology
  • Protein-Tyrosine Kinases / physiology
  • RNA, Messenger / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Reactive Oxygen Species / physiology
  • Receptors, Serotonin / physiology*
  • Signal Transduction / physiology
  • Transforming Growth Factor beta / genetics
  • Transforming Growth Factor beta / metabolism*
  • Virulence Factors, Bordetella / pharmacology


  • RNA, Messenger
  • Reactive Oxygen Species
  • Receptors, Serotonin
  • Transforming Growth Factor beta
  • Virulence Factors, Bordetella
  • NADPH Oxidases
  • Protein-Tyrosine Kinases
  • Protein Serine-Threonine Kinases
  • Protein Kinase C
  • Calcium-Calmodulin-Dependent Protein Kinases
  • MAP Kinase Kinase 1
  • Mitogen-Activated Protein Kinase Kinases
  • GTP-Binding Proteins