HUMAN HIGH-DENSITY-LIPOPROTEINS STIMULATE ENDOTHELIN-1 RELEASE BY CULTURED HUMAN RENAL PROXIMAL TUBULAR CELLS.
1315 - 1321.
The vasoconstrictive and mitogenic actions of endothelins have been implicated in the pathogenesis of progressive renal disease. In the present study, we have assessed whether plasma high density lipoproteins (HDL), the major filtered urinary lipoprotein in nephrotic states, can influence endothelin-1 (ET-1) production by cultured human renal proximal tubular cells. Human HDL was found to stimulate ET-1 secretion up to fourfold in a dose- and time-dependent manner; the effect was greater in subconfluent cultures than in confluent ones. There was little difference between the stimulatory effect of HDL(2) and the major HDL subclass, HDL(3). Preincubation of the cells with albumin did not abolish the HDL effect, while partially- or fully-delipidated HDL(3) largely reproduced the effect of whole HDL(3). These findings suggest that stimulation of ET-1 secretion was not simply due to protein or lipid repletion of the cells. Rather, the effect was mediated by HDL apolipoproteins, although binding to the HDL receptors involved in cellular cholesterol homeostasis was not required as tetranitromethane-modified HDL(3) was an equally effective agonist of ET-1 release. Apolipoprotein (ape) A-I was indirectly implicated in the process since modified HDL(3) in which apoA-II largely replaced apoA-I was less potent than HDL(3). A one hour exposure of the cells to HDL(3) was sufficient to activate ET-1 production for the following 12 hours, although maximum activation required six hours. The activation process appeared to be independent of both cyclic AMP and protein kinase C (PKC): HDL(3) and phorbol myristate acetate had an additive effect; PKC-depleted cells remained responsive to HDL(3); and the PKC inhibitor, staurosporine, did not reduce HDL(3), stimulation of ET-1 production. We conclude that the apolipoprotein constituents of HDL(3) enhance ET-1 secretion by cultured renal tubular cells via a novel PKC-independent pathway. Whether this action of human HDL on tubular ET-1 production also occurs in vivo merits investigation, since it may have pathophysiological significance for the progressive tubulointerstitial fibrosis associated with chronic proteinuria.
|Title:||HUMAN HIGH-DENSITY-LIPOPROTEINS STIMULATE ENDOTHELIN-1 RELEASE BY CULTURED HUMAN RENAL PROXIMAL TUBULAR CELLS|
|Keywords:||PLACENTAL-LACTOGEN RELEASE, TRYPANOSOMA-BRUCEI-BRUCEI, PROTEIN-KINASE-C, HUMAN TROPHOBLAST CELLS, SMOOTH-MUSCLE CELLS, APOLIPOPROTEIN-A-I, EPITHELIAL-CELLS, PEPTIDE ENDOTHELIN, KIDNEY, PROLIFERATION|
|UCL classification:||UCL > School of Life and Medical Sciences > Faculty of Medical Sciences > Medicine (Division of)|
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