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Renal damage and salt-dependent hypertension in aged transgenic mice overexpressing endothelin-1
T Shindo1, H Kurihara, K Maemura
1Department of Cardiovascular Medicine, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
Insights
Chronic overproduction of endothelin-1 (ET-1) in mice led to kidney damage and salt-dependent hypertension, suggesting ET-1 primarily affects renal function rather than directly causing hypertension.
Area of Science:
- Cardiovascular Physiology
- Renal Pathophysiology
- Endocrinology
Background:
- Endothelin-1 (ET-1) plays a role in cardiovascular diseases like hypertension and renal failure.
- The exact role of endogenous ET-1 system activation in these conditions remains unclear.
- Understanding ET-1's effects requires studying its overexpression phenotypes.
Purpose of the Study:
- To investigate the physiological and pathological consequences of chronic endothelin-1 (ET-1) overproduction.
- To determine if ET-1 overproduction is a primary cause of cardiovascular ailments.
- To elucidate the specific tissues and systems affected by sustained ET-1 elevation.
Main Methods:
- Generation of two transgenic mouse lines overexpressing the ET-1 gene.
- Monitoring of body weight, fur density, and ET-1 levels in plasma, heart, kidney, and aorta.
- Histological examination of visceral organs and assessment of renal function (creatinine clearance, urinary protein) and blood pressure in young and aged mice.
Main Results:
- Transgenic mice showed reduced body weight, fur density, and 2-4 fold increases in ET-1 levels.
- Young mice had no apparent abnormalities or elevated blood pressure.
- Aged mice developed renal pathologies (fibrosis, cysts, glomerulosclerosis, arteriolar narrowing), decreased creatinine clearance, proteinuria, and salt-dependent hypertension.
Conclusions:
- Mild, chronic endothelin-1 (ET-1) overproduction does not primarily cause hypertension.
- Sustained ET-1 elevation induces progressive renal damage.
- Kidney damage resulting from ET-1 overproduction leads to susceptibility to salt-induced hypertension.
Abstract:
The recent development of endothelin-1 (ET-1) antagonists and their potential use in the treatment of human disease raises questions as to the role of ET-1 in the pathophysiology of such cardiovascular ailments as hypertension, heart failure, renal failure and atherosclerosis. It is still unclear, for example, whether activation of an endogenous ET-1 system is itself the primary cause of any of these ailments. In that context, the phenotypic manifestations of chronic ET-1 overproduction may provide clues about the tissues and systems affected by ET-1. We therefore established two lines of transgenic mice overexpressing the ET-1 gene under the direction of its own promoter. These mice exhibited low body weight, diminished fur density and two- to fourfold increases in the ET-1 levels measured in plasma, heart, kidney and aorta. There were no apparent histological abnormalities in the visceral organs of young (8 weeks old) transgenic mice, nor was their blood pressure elevated. In aged (12 months old) transgenic mice, however, renal manifestations, including prominent interstitial fibrosis, renal cysts, glomerulosclerosis and narrowing of arterioles, were detected. These pathological changes were accompanied by decreased creatinine clearance, elevated urinary protein excretion and salt-dependent hypertension. It thus appears that mild, chronic overproduction of ET-1 does not primarily cause hypertension but triggers damaging changes in the kidney which lead to the susceptibility to salt-induced hypertension.