Effects of mineralocorticoid receptor gene disruption on the components ofthe renin-angiotensin system in 8-day-old mice

Targeted disruption of mineralocorticoid receptor (MR) gene results in pseu dohypoaldosteronism type I with failure to thrive, severe dehydration, hype rkalemia, hyponatremia, and high plasma levels of renin, angiotensin II, an d aldosterone. In this study, mRNA expression of the different components o f the renin-angiotensin system (RAS) were evaluated in liver, lung, heart, kidney and adrenal gland to assess their response to a state of extreme sod ium depletion. Angiotensinogen, renin, angiotensin-l converting enzyme, and angiotensin II receptor (AT(1) and AT(2)) mRNA expressions were determined by Northern blot and RT-PCR analysis. Furthermore, in situ hybridization a nd immunohistochemistry allowed us to identify the cell types involved in t he variation of the RAS component expression. In the heterozygous mice (MR/-), compared with wild-type mice (MR+/+), there was no significant variati on of any mRNA of the RAS components. In MR knockout mice (MR-/-), compared with wild-type mice, there were significant increases in the expression le vel of several RAS components. In the liver, angiotensinogen and AT, recept or mRNA expressions were moderately stimulated. In the kidney, renin mRNA w as increased up to 10-fold and in situ hybridization showed a marked recrui tment of renin-producing cells; however, the levels of angiotensin-l conver ting enzyme mRNA and AT, mRNA were not changed. Interestingly, in adrenal g land, renin expression was also strongly up-regulated in a thickened zona g lomerulosa, whereas AT, mRNA expression remained unchanged. Altogether, the se results demonstrate that in the MR knockout mice model, RAS component ex pressions are differentially altered, renin being the most stimulated compo nent. Angiotensinogen and AT(1) in the liver are also increased, but the ot her elements of the RAS are not affected.