title: Hypertrophy in the Distal Convoluted Tubule of an 11β-Hydroxysteroid Dehydrogenase Type 2 Knockout Model.
abstract: Na(+) transport in the renal distal convoluted tubule (DCT) by the thiazide-sensitive NaCl cotransporter (NCC) is a major determinant of total body Na(+) and BP. NCC-mediated transport is stimulated by aldosterone, the dominant regulator of chronic Na(+) homeostasis, but the mechanism is controversial. Transport may also be affected by epithelial remodeling, which occurs in the DCT in response to chronic perturbations in electrolyte homeostasis. Hsd11b2(-/-) mice, which lack the enzyme 11β-hydroxysteroid dehydrogenase type 2 (11βHSD2) and thus exhibit the syndrome of apparent mineralocorticoid excess, provided an ideal model in which to investigate the potential for DCT hypertrophy to contribute to Na(+) retention in a hypertensive condition. The DCTs of Hsd11b2(-/-) mice exhibited hypertrophy and hyperplasia and the kidneys expressed higher levels of total and phosphorylated NCC compared with those of wild-type mice. However, the striking structural and molecular phenotypes were not associated with an increase in the natriuretic effect of thiazide. In wild-type mice, Hsd11b2 mRNA was detected in some tubule segments expressing Slc12a3, but 11βHSD2 and NCC did not colocalize at the protein level. Thus, the phosphorylation status of NCC may not necessarily equate to its activity in vivo, and the structural remodeling of the DCT in the knockout mouse may not be a direct consequence of aberrant corticosteroid signaling in DCT cells. These observations suggest that the conventional concept of mineralocorticoid signaling in the DCT should be revised to recognize the complexity of NCC regulation by corticosteroids.
authors.affiliation: British Heart Foundation Centre for Cardiovascular Science and robert.hunter@ed.ac.uk.
authors.forename: Robert W
authors.initials: RW
authors.lastname: Hunter
authors.affiliation: British Heart Foundation Centre for Cardiovascular Science and.
authors.forename: Jessica R
authors.initials: JR
authors.lastname: Ivy
authors.affiliation: Centre for Integrative Physiology, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Peter W
authors.initials: PW
authors.lastname: Flatman
authors.affiliation: British Heart Foundation Centre for Cardiovascular Science and.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Kenyon
authors.affiliation: British Heart Foundation Centre for Cardiovascular Science and.
authors.forename: Eilidh
authors.initials: E
authors.lastname: Craigie
authors.affiliation: British Heart Foundation Centre for Cardiovascular Science and.
authors.forename: Linda J
authors.initials: LJ
authors.lastname: Mullins
authors.affiliation: British Heart Foundation Centre for Cardiovascular Science and.
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Bailey
authors.affiliation: British Heart Foundation Centre for Cardiovascular Science and.
authors.forename: John J
authors.initials: JJ
authors.lastname: Mullins
mesh_terms: D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2 / Q000378:metabolism / Q000494:pharmacology*; D000704:Analysis of Variance; D000818:Animals; D002478:Cells, Cultured; D018076:DNA, Complementary / Q000032:analysis; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects; D005260:Female; D006984:Hypertrophy / Q000473:pathology; D007686:Kidney Tubules, Distal / Q000187:drug effects / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010766:Phosphorylation / Q000187:drug effects*; D016133:Polymerase Chain Reaction / Q000379:methods; D012313:RNA / Q000032:analysis; D011897:Random Allocation; D049992:Sodium Chloride Symporters / Q000378:metabolism*; D057900:Transcytosis / Q000502:physiology
chemical_list: D018076:DNA, Complementary; D049992:Sodium Chloride Symporters; D012313:RNA; D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2
keywords: distal tubule; epithelial cells; epithelial sodium transport; hypertrophy; renal tubular