VASCULAR AND GLOMERULAR EXPRESSION OF ENDOTHELIN-1 IN NORMAL HUMAN KIDNEY

To understand better the function of endothelin-1 (ET-1) in renal phys iology, we examined vascular and glomerular expression of ET-1 in norm al human kidney and in lupus nephritis. Immunohistochemical analysis r evealed that renal endothelium of glomeruli, arteries, veins, and capi llaries 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. H owever, mesangial staining for ET-1 was elevated in patients with lupu s nephritis, suggesting that under certain conditions mesangial cells elaborate ET-1. Indeed cultured human mesangial cells from normal subj ects secreted ET-1 peptide. ET-1 secretion was augmented by the protei n kinase C activator phorbol ester and by transforming growth factor-b eta 1 (TGF-beta 1), a cytokine implicated in the development of glomer ulosclerosis. 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- beta 1, phorbol ester, or ectopic expression of protein kinase pi. Cul tured human mesangial cells have both ETA and ETB receptors that contr ibute to ET-1-stimulated mitogenesis. Taken together, these results de monstrate that ET-1 is expressed at sites where paracrine or autocrine signaling by ET-1 might control renal vasoconstriction, glomerular fi ltration rate, and remodeling of the glomerulus in renal disease.