Increased mineralocorticoid activity in obese Zucker rats is independent of the renin-angiotensin system and hepatic steroid metabolism.

Abstract

Hypertension in obese Zucker rats is associated with raised plasma aldosterone, suppressed renin and increased hypothalamo-pituitary-adrenal activity. We investigated the possible causes and consequences of these associations by comparing adrenal gene expression and urinary electrolyte and steroid excretion patterns in lean and obese rats. Groups (n=11) of adult male lean and obese Zucker rats were held in metabolism cages for 7 days. Urine collected over the last 2 days was analysed for electrolytes and steroid content by flame photometry, ELISA and LCMS. Urine volumes, sodium, potassium and creatinine were higher in obese vs lean rats (P<0.05): ratios of Na/creatinine and K/creatinine were lower (P<0.01) but Na/K was unaffected. Urinary aldosterone and 18OH deoxycorticosterone were not significantly different. Urinary corticosterone was slightly higher (1.5 fold, P<0.001) in obese vs lean rats in agreement with previous evidence of adrenocortical cell hypertrophy. Deoxycorticosterone (11_ hydroxylase precursor) and 11 dehydrocorticosterone (11_ hydroxysteroid dehydrogenase product) were markedly higher (3.3 and 2.6 fold respectively, P<0.001). We considered whether these changes could be attributed to intra-adrenal differences in the expression of enzymes involved in the synthesis and metabolism of corticosterone. Cyp11b1 (11_ hydroxylase) was increased and 5alpha reductase type 1, 11_HSD1 and 2 mRNA differences were not statistically significant. We conclude that extra-adrenal metabolism of corticosterone is compensated by HPA-mediated adrenal hypertrophy. Increased antinatriuretic activity and suppressed renin can be attributed to higher aldosterone and/or deoxycorticosterone levels or impaired renal 11_HSD2 activity. These differences are not caused by changes in the pattern of adrenal steroidogenesis nor are they likely to be due reduced hepatic metabolism of mineralocorticoid hormones. Raised plasma aldosterone:renin ratios in obese Zucker rats could be explained by a novel adipose factor(s) that has recently been shown to stimulate aldosterone synthesis by Wnt signalling effects on StAR protein.