Endocrine Abstracts

We investigated ACTH-induced hypertension in mice by studying renal function in vivo and by analysing renal gene expression by microarray and RT PCR methods. During two weeks sc infusion with Synacthen, mean blood pressure in adult male mice increased (89±5 vs 110±2 mmHg), and plasma corticosterone, adrenal weights and drinking rate increased by 5, 2 and 2.5-fold respectively (P<0.01); renal mass was unaffected. Greater mineralocorticoid activity was indicated by hypokalaemia, increased amiloride sensitive sodium excretion and a 2-fold increase in renal ENac expression (P<0.05). Increases in haematocrit, plasma osmolality and glomerular filtration rate (P<0.01) were attributed to glucocorticoid excess. We used Affymetrix mouse genome 430 RNA chips (n=3) to analyse RNA extracted from whole kidneys taken at the end of the infusion. Genes expressed below background levels and those with one anomalous value were filtered out. This excluded many genes which are thought to be regulated by adrenal steroids whose expression is confined to specific cell types. Of the 12,000 remaining genes, 46 genes were down-regulated more than 2-fold and 27 were up-regulated more than 2-fold. Up-regulated genes included serum glucocorticoid-regulated-kinase (Sgk,4.1-fold) which is induced by both mineralo and glucocorticoids, aquaporin 4 (Aqp4, 3.6-fold) which mediates water reabsorption in the collecting duct, a calcium binding protein (Calb1, 3.3-fold) and an amino-acid transporter (Slc7a12, 18-fold). Glucocorticoid and mineralocorticoid receptor genes and genes encoding components of the renin-angiotensin system were unaffected. Down-regulated genes included 11-hydroxysteroid dehydrogenase type 1 (Hsd11b1, −2.7-fold) and solute transporters and genes known to be expressed in the proximal tubule (Slc22a8, −2.8; Slc6a15, −2.3; Slc7a13,−2.5; Slc9a8, −2.3; Slc01a1, −4.8; Car3, −3.7). The SA gene, known to be elevated in other models of hypertension, was down-regulated (Sah, −8.3). We conclude that many of the gene changes represent counter-regulatory mechanisms to oppose the pathophysiological effects of adrenal steroids.