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Thesis (Ph.D.)--University of Delaware, 2009. / Principal faculty advisor: William B. Farquhar, Dept. of Health, Nutrition, & Exercise Sciences. Includes bibliographical references.

Thesis (M.S.)--University of Delaware, 2005. / Principal faculty advisor: William B. Farquhar, Dept. of Health and Exercise Science. Includes bibliographical references.

Lack of the enzyme 11β-hydroxysteroid dehydrogenase type 2 (11βHSD2) causes the syndrome of apparent mineralocorticoid excess (AME): low-renin hypertension, renal sodium (Na +) retention, hypokalaemic alkalosis and polyuria. This rare autosomal recessive disorder is observed in human kindreds carrying mutations in the HSD11B2 gene. Genetically modified mice, in which the homologue Hsd11b2 is rendered non-functional, have been used to study the pathogenesis of AME. Hitherto, data obtained from humans and mice have suggested that the physiological phenotype is a consequence of enhanced reabsorption of Na + through the epithelial sodium channel (ENaC) in the renal connecting tubule (CNT) and collecting duct. However, Hsd11b2 null mice exhibit epithelial hypertrophy in a different nephron segment, namely the distal convoluted tubule (DCT). The studies described herein aimed to characterise this structural phenotype and to examine the consequences for renal Na + reabsorption in AME. Hsd11b2 null mice exhibited hypertrophy and hyperplasia in the DCT, with an elevated rate of epithelial cell proliferation in this nephron segment at 60 days of age. Hsd11b2 null kidneys contained greater quantities of the thiazide-sensitive NaCl co-transporter (NCC), the dominant Na + transporter protein in the DCT. They also contained greater quantities of the phosphorylated forms of NCC that are associated with NaCl transport activity. Despite this, there was no increase in the proportion of filtered Na + that was reabsorbed in the DCT. This was assessed in anaesthetised mice, using clearance methodology to measure the thiazide-induced increment in the fractional excretion of Na + (FENa) during continuous ENaC blockade. Wild-type DCTs did not express 11βHSD2; therefore the structural and molecular changes were not a direct consequence of the loss of 11βHSD2 in affected cells. The discussion examines the likely mechanisms causing structural remodelling in the distal renal tubule of Hsd11b2 null kidneys and potential explanations for the dissociation between structural and functional phenotypes in the DCT. There are implications for our understanding of the cellular and molecular mechanisms underlying various renal phenomena including structural remodelling in the distal tubule, resolution of the ‘aldosterone paradox’ and escape from chronic aldosterone excess.