Serotonin 5-HT_2Areceptor induces TGF-β1 expression in mesangial cells via ERK: proliferative and fibrotic signals

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-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-HT2A 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.

Diabetes Autoantibodies Mediate Neural- and Endothelial Cell- Inhibitory Effects Via 5-Hydroxytryptamine- 2 Receptor Coupled to Phospholipase C/Inositol Triphosphate/Ca2+ Pathway

“…These data suggest that immune complexes in diabetic CKD protein-A eluates were less stable (in dilute solution) compared to component IgG . More study is needed to determine whether diabetic CKD autoantibodies may also induce proliferation in mesangial cells, via 5-HT-2A receptors coupled to ERK signaling [24].…”

Platelets in Early Antibody-Mediated Rejection of Renal Transplants

“…41,42 More prolonged effects of serotonin include the induction of fibrotic responses. 43 In conjunction with the release of chemokines, the expression of P-selectin on activated platelets promotes interactions with macrophages. 44 Immunohistology of both mouse and human renal allografts showed P-selectin expressing platelets attached to macrophages in capillaries and venules.…”

Absence of major fibrotic adverse events in hyperprolactinemic patients treated with cabergoline

“…Excessive proliferation of fibromyoblasts could lead to overgrowth valvopathy, but in theory, it could also lead to pleuropulmonary and retroperitoneal fibrosis (42)(43)(44). The potent 5-HT 2B receptor agonistic characteristic of cabergoline seems to be the key in the pathogenic cascade, and it is likely to be a drug class effect.…”