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Am J Physiol Renal Physiol 276: F922-F930, 1999;
0363-6127/99 $5.00
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Vol. 276, Issue 6, F922-F930, June 1999

Serotonin 5-HT2A receptor induces TGF-beta 1 expression in mesangial cells via ERK: proliferative and fibrotic signals

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

Department of Medicine, Nephrology Division, Medical University of South Carolina and the Ralph H. Johnson Veterans Affairs Medical Center, Charleston, South Carolina 29425

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-beta 1 (TGF-beta 1) 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-beta 1 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-beta 1 protein, validating the mRNA studies and demonstrating that 5-HT potently activates ERK and induces TGF-beta 1 mRNA and protein in mesangial cells. Mapping studies strongly supported relative positions of the components of the signaling cascade as follow: 5-HT2A receptor right-arrow PKC right-arrow NAD(P)H oxidase/reactive oxygen species right-arrow MEK right-arrow ERK right-arrow TGF-beta 1 mRNA. These studies demonstrate that mitogenic signaling components (PKC, MEK, and oxidants) are directly linked to the regulation of TGF-beta 1, a key mediator of fibrosis. Thus a single stimulus can direct both proliferative and fibrotic signals in renal mesangial cells.

proliferation; fibrosis; mesangial cell; serotonin; transforming growth factor


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