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1 Department of Medicine,
To understand better
the function of endothelin-1 (ET-1) in renal physiology, we examined
vascular and glomerular expression of ET-1 in normal human kidney and
in lupus nephritis. Immunohistochemical analysis revealed that renal
endothelium of glomeruli, arteries, veins, and capillaries expressed
ET-1. Endothelial cells were the principal source of glomerular ET-1;
positive immunostaining was detected only rarely in mesangial cells and
vascular smooth muscle cells from normal kidney. However, mesangial
staining for ET-1 was elevated in patients with lupus nephritis,
suggesting that under certain conditions mesangial cells elaborate
ET-1. Indeed cultured human mesangial cells from normal
subjects secreted ET-1 peptide. ET-1 secretion was augmented by the
protein kinase C activator phorbol ester and by transforming growth
factor-
1 (TGF-
1), a cytokine implicated in the development of
glomerulosclerosis. Transient transfection of cultured mesangial cells
with a preproET-1 reporter construct showed that the preproET-1
promoter is transcriptionally active in mesangial cells and is
stimulated by TGF-
1, phorbol ester, or ectopic expression of protein
kinase
1. Cultured human mesangial cells have both
ETA and
ETB receptors that contribute to
ET-1-stimulated mitogenesis. Taken together, these results demonstrate
that ET-1 is expressed at sites where paracrine or autocrine signaling
by ET-1 might control renal vasoconstriction, glomerular filtration
rate, and remodeling of the glomerulus in renal disease.
vasoactive peptides; G protein-coupled receptors; renal hemodynamics
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