TIME-COURSE AND LOCALIZATION OF ENDOTHELIN-1 GENE-EXPRESSION IN A MODEL OF RENAL-DISEASE PROGRESSION

Experimental and human proteinuric glomerulopathies are associated wit h tubulo-interstitial injury that correlates with the decline of renal function even better than glomerular lesions do. Mechanism(s) leading to tubulo-interstitial damage are unknown. It has been proposed that excessive reabsorption of filtered proteins activates renal cells to p roduce vasoactive and inflammatory molecules including endothelin-1. T he aim of the present study was twofold: we first evaluated the cellul ar origin of excessive renal endothelin-1 production in the renal mass reduction model and then related endothelin-1 distribution to the dev elopment of kidney lesions, Four groups of renal mass reduction (n = 1 5) and four groups of control rats (n = 5) were studied at 7, 14, 21, and 28 days after surgery, Urinary proteins in renal mass reduction ra ts were comparable with controls at day 7 but became significantly hig her thereafter. Renal mass reduction rats first developed tubulo-inter stitial changes, which were already evident at day 14 in the majority of them, At 28 days, renal mass reduction rats also developed glomerul osclerosis. A parallel increase of renal endothelin-1 gene expression and synthesis of the corresponding peptide in renal mass reduction rat s versus controls was observed from day 14. Nonradioactive in situ hyb ridization confirmed a pattern of endothelin-1 mRNA consistent with th e distribution of lesions. At day 14, endothelin-1 staining was strong er in renal mass reduction than in control kidneys and mainly localize d to the cytoplasm of tubular cells, whereas glomeruli were negative. At day 28, endothelin-1 expression further increased in renal mass red uction rats as compared with controls, and the staining was apparent a lso in glomeruli. Thus, in renal mass reduction, a progressive up-regu lation of endothelin-1 occurs during the development of renal injury, that first involves the tubules and, only in a subsequent phase, the g lomeruli.