title: Endothelin-1 increases collagen accumulation in renal mesangial cells by stimulating a chemokine and cytokine autocrine signaling loop.
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.
authors.affiliation: Department of Medicine, Case Western Reserve University, Cleveland, Ohio 44106, USA. mss5@case.edu
authors.forename: Michael S
authors.initials: MS
authors.lastname: Simonson
authors.forename: Faramarz
authors.initials: F
authors.lastname: Ismail-Beigi
mesh_terms: D057134:Antibodies, Neutralizing / Q000494:pharmacology; D019898:Autocrine Communication / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D003094:Collagen / Q000096:biosynthesis; D019332:Endothelin-1 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism*; D050527:Mesangial Cells / Q000166:cytology / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D000093242:Interleukin-6 Inhibitors
chemical_list: D057134:Antibodies, Neutralizing; D018932:Chemokine CCL2; D003094:Collagen; D019332:Endothelin-1; D015850:Interleukin-6; D000093242:Interleukin-6 Inhibitors; C111835:CCL2 protein, human; C508600:IL6 protein, human