Vascular and glomerular expression of endothelin-1 in normal human kidney.
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-beta1 (TGF-beta1), 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-beta1, phorbol ester, or ectopic expression of protein kinase beta1. 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.
Herman
W H
WH
Department of Medicine, Division of Nephrology, School of Medicine, Case Western Reserve University and University Hospitals of Cleveland, Cleveland, Ohio 44106, USA.
Emancipator
S N
SN
Rhoten
R L
RL
Simonson
M S
MS
D002478:Cells, Cultured; D019332:Endothelin-1 / Q000096:biosynthesis*; D004730:Endothelium, Vascular / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D005920:Glomerular Mesangium / Q000378:metabolism; D006801:Humans; D007678:Kidney Glomerulus / Q000378:metabolism*; D008181:Lupus Nephritis / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000378:metabolism; D016133:Polymerase Chain Reaction; D011493:Protein Kinase C / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis; D011994:Recombinant Proteins / Q000096:biosynthesis; D012079:Renal Circulation / Q000502:physiology*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014158:Transcription, Genetic; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000494:pharmacology
D019332:Endothelin-1; D012333:RNA, Messenger; D011994:Recombinant Proteins; D016212:Transforming Growth Factor beta; D011493:Protein Kinase C; D013755:Tetradecanoylphorbol Acetate