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21169360
Endothelin-1 increases collagen accumulation in renal mesangial cells by stimulating a chemokine and cytokine autocrine signaling loop.

J Biol Chem, 2011/4/01;286(13):11003-8.

Simonson MS[1], Ismail-Beigi F

Affiliations

PMID: 21169360DOI: 10.1074/jbc.M110.190793

Impact factor: 5.486

Abstract
Endothelin-1 (ET-1), a potent vasoconstrictor, has been implicated in the pathogenesis of collagen accumulation, extracellular matrix remodeling, and renal and cardiac fibrosis in diabetes. However, the mechanism by which ET-1 promotes collagen accumulation remains unclear. Here, we analyzed the gene expression profile of ET-1-stimulated mesangial cells to identify determinants of collagen accumulation. In human mesangial cells (a microvascular pericyte that secretes excess collagen in diabetic glomerulosclerosis), ET-1 increased mRNA and protein for MCP-1 (macrophage chemoattractant protein-1) and IL-6. ET-1-induced MCP-1 and IL-6 mRNAs and proteins were blocked by an ET(A) (but not ET(B)) receptor antagonist. ET-1/ET(A) receptor signaling evoked a 7.4-fold increase in collagen accumulation. Exogenous addition of either recombinant MCP-1 or IL-6 increased collagen accumulation by 3.5-fold. Co-stimulation with both MCP-1 and IL-6 did not elevate collagen accumulation further. Neither an MCP-1-neutralizing antibody nor an MCP-1 receptor antagonist inhibited ET-1-induced collagen accumulation. Similarly, neutralizing antibodies against IL-6 or the gp130 subunit of the IL-6 receptor did not attenuate ET-1-induced collagen accumulation. However, co-incubation with MCP-1- and IL-6-neutralizing antibodies inhibited ET-1-induced collagen accumulation by 52%, suggesting a robust autocrine loop wherein MCP-1 and IL-6 are redundant. Taken together, these results demonstrate that an autocrine signaling loop involving MCP-1 and IL-6 contributes to ET-1-induced collagen accumulation.
MeSH terms
Antibodies, Neutralizing; Autocrine Communication; Cells, Cultured; Chemokine CCL2; Collagen; Endothelin-1; Humans; Interleukin-6; Mesangial Cells; Signal Transduction
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