Time course and localization of endothelin-1 gene expression in a model of renal disease progression.
Experimental and human proteinuric glomerulopathies are associated with 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 produce vasoactive and inflammatory molecules including endothelin-1. The aim of the present study was twofold: we first evaluated the cellular origin of excessive renal endothelin-1 production in the renal mass reduction model and then related endothelin-1 distribution to the development of kidney lesions. Four groups of renal mass reduction (n = 15) 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 rats were comparable with controls at day 7 but became significantly higher thereafter. Renal mass reduction rats first developed tubulo-interstitial changes, which were already evident at day 14 in the majority of them. At 28 days, renal mass reduction rats also developed glomerulosclerosis. A parallel increase of renal endothelin-1 gene expression and synthesis of the corresponding peptide in renal mass reduction rats versus controls was observed from day 14. Nonradioactive in situ hybridization confirmed a pattern of endothelin-1 mRNA consistent with the distribution of lesions. At day 14, endothelin-1 staining was stronger in renal mass reduction than in control kidneys and mainly localized to the cytoplasm of tubular cells, whereas glomeruli were negative. At day 28, endothelin-1 expression further increased in renal mass reduction rats as compared with controls, and the staining was apparent also in glomeruli. Thus, in renal mass reduction, a progressive up-regulation of endothelin-1 occurs during the development of renal injury, that first involves the tubules and, only in a subsequent phase, the glomeruli.
Bruzzi
I
I
Mario Negri Institute for Pharmacological Research, Bergamo, Italy.
Corna
D
D
Zoja
C
C
Orisio
S
S
Schiffrin
E L
EL
Cavallotti
D
D
Remuzzi
G
G
Benigni
A
A
D000818:Animals; D018450:Disease Progression; D019332:Endothelin-1 / Q000235:genetics*; D015870:Gene Expression / Q000502:physiology*; D017403:In Situ Hybridization; D007668:Kidney / Q000378:metabolism; D007674:Kidney Diseases / Q000235:genetics* / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D009392:Nephrectomy / Q000379:methods; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012016:Reference Values; D013997:Time Factors; D014018:Tissue Distribution
D019332:Endothelin-1; D012333:RNA, Messenger