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1 Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC, USA; Siberian Division, Russian Academy of Sciences, Institute of Cytology and Genetics, Novosibirsk, Russian
2 Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC, USA
3 Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC, USA; Department of Cellular and Molecular Physiology, University of North Carolina, Chapel Hill, NC, USA
4 Department of Pediatrics, University of Virginia, Charlottesville, VA, USA
* To whom correspondence should be addressed. E-mail: jenny_langenbach{at}med.unc.edu.
To explore the effects of decreased amounts or absence of aldosterone, we have disrupted the gene coding for aldosterone synthase (AS) in mice and investigated blood pressure and kidney function in AS+/+, AS+/- and AS-/- mice. AS+/- mice have normal blood pressures and show no abnormalities in electrolytes or kidney gene expression but they have significantly higher than normal urine volume and lower urine osmolality. In contrast, the AS-/- mice have low blood pressure, abnormal electrolyte homeostasis (increased plasma concentrations of K+, Ca2+ and Mg2+ and decreased concentrations of HCO- 3 and Cl- but no difference in the plasma Na+ level), and disturbances in water metabolism (higher urine output, decreased urine osmolality, and impaired urine concentrating and diluting ability). Absence of aldosterone in the AS-/- mice induced several compensatory changes: an increased food intake/body weight ratio, an elevated plasma concentration of glucocorticoids, and strong activation of the renin-angiotensin system. Parallel with the markedly increased synthesis and release of renin, the AS-/- mice showed increased expression of COX-2 in macula densa. On salt supplementation, plasma electrolyte concentrations and kidney renin and COX-2 levels became similar to those of wild type mice, but the lower blood pressure of the AS-/- mice was not corrected. Thus, absence of aldosterone in AS-/- mice results in impairment of sodium reabsorption in the distal nephron, decreased blood pressure, and strong RAS activation. Our data show the substantial correction of these abnormalities, except the low blood pressure, by high dietary salt does not depend on aldosterone.
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