Serotonin 5-HT(2A) receptor induces TGF-β1 expression in mesangial cells via ERK: Proliferative and fibrotic signals

Jasjit S. Grewal, Yurii V. Mukhin, Maria N. Garnovskaya, John R. Raymond, Eddie L. Greene

Research output: Contribution to journalArticle

122 Scopus citations

Abstract

We examined the links between fibrotic and proliferative pathways for the 5-HT(2A) receptor in rat mesangial cells. Serotonin (5-hydroxytryptamine, 5-HT) induced transforming growth factor-β1 (TGF-β1) 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 α-lipoic acid, and mimicked by direct application of H2O2. TGF-β1 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-β1 protein, validating the mRNA studies and demonstrating that 5-HT potently activates ERK and induces TGF- β1 mRNA and protein in mesangial cells. Mapping studies strongly supported relative positions of the components of the signaling cascade as follow: 5- HT(2A) receptor → PKC → NAD(P)H oxidase/reactive oxygen species → MEK → ERK → TGF-β1 mRNA. These studies demonstrate that mitogenic signaling components (PKC, MEK, and oxidants) are directly linked to the regulation of TGF-β1, a key mediator of fibrosis. Thus a single stimulus can direct both proliferative and fibrotic signals in renal mesangial cells.

Original languageEnglish (US)
Pages (from-to)F922-F930
JournalAmerican Journal of Physiology - Renal Physiology
Volume276
Issue number6 45-6
DOIs
StatePublished - Jun 1996

Keywords

  • Fibrosis
  • Mesangial cell
  • Proliferation
  • Serotonin
  • Transforming growth factor

ASJC Scopus subject areas

  • Physiology
  • Urology

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