title: Primary aldosteronism and impaired natriuresis in mice underexpressing TGFβ1.
abstract: To uncover the potential cardiovascular effects of human polymorphisms influencing transforming growth factor β1 (TGFβ1) expression, we generated mice with Tgfb1 mRNA expression graded in five steps from 10% to 300% normal. Adrenal expression of the genes for mineralocorticoid-producing enzymes ranged from 50% normal in the hypermorphs at age 12 wk to 400% normal in the hypomorphs accompanied with proportionate changes in plasma aldosterone levels, whereas plasma volumes ranged from 50% to 150% normal accompanied by marked compensatory changes in plasma angiotensin II and renin levels. The aldosterone/renin ratio ranged from 0.3 times normal in the 300% hypermorphs to six times in the 10% hypomorphs, which have elevated blood pressure. Urinary output of water and electrolytes are markedly decreased in the 10% hypomorphs without significant change in the glomerular filtration rate. Renal activities for the Na(+), K(+)-ATPase, and epithelial sodium channel are markedly increased in the 10% hypomorphs. The hypertension in the 10% hypomorphs is corrected by spironolactone or amiloride at doses that do not change blood pressure in wild-type mice. Thus, changes in Tgfb1 expression cause marked progressive changes in multiple systems that regulate blood pressure and fluid homeostasis, with the major effects being mediated by changes in adrenocortical function.
authors.affiliation: Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC 27599, USA. mkakoki@med.unc.edu
authors.forename: Masao
authors.initials: M
authors.lastname: Kakoki
authors.forename: Oleh M
authors.initials: OM
authors.lastname: Pochynyuk
authors.forename: Catherine M
authors.initials: CM
authors.lastname: Hathaway
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Tomita
authors.forename: John R
authors.initials: JR
authors.lastname: Hagaman
authors.forename: Hyung-Suk
authors.initials: HS
authors.lastname: Kim
authors.forename: Oleg L
authors.initials: OL
authors.lastname: Zaika
authors.forename: Mykola
authors.initials: M
authors.lastname: Mamenko
authors.forename: Yukako
authors.initials: Y
authors.lastname: Kayashima
authors.forename: Kota
authors.initials: K
authors.lastname: Matsuki
authors.forename: Sylvia
authors.initials: S
authors.lastname: Hiller
authors.forename: Feng
authors.initials: F
authors.lastname: Li
authors.forename: Longquan
authors.initials: L
authors.lastname: Xu
authors.forename: Ruriko
authors.initials: R
authors.lastname: Grant
authors.forename: Alejandro M
authors.initials: AM
authors.lastname: Bertorello
authors.forename: Oliver
authors.initials: O
authors.lastname: Smithies
mesh_terms: D000450:Aldosterone / Q000097:blood*; D000584:Amiloride / Q000494:pharmacology; D000804:Angiotensin II / Q000097:blood; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D017931:DNA Primers / Q000235:genetics; D005786:Gene Expression Regulation / Q000235:genetics / Q000502:physiology*; D005919:Glomerular Filtration Rate / Q000502:physiology; D006929:Hyperaldosteronism / Q000209:etiology* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009318:Natriuresis / Q000502:physiology*; D016133:Polymerase Chain Reaction; D012083:Renin / Q000097:blood; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism; D013148:Spironolactone / Q000494:pharmacology; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism*; D016482:Urinalysis
chemical_list: D017931:DNA Primers; D053773:Transforming Growth Factor beta1; D000804:Angiotensin II; D013148:Spironolactone; D000450:Aldosterone; D000584:Amiloride; D012083:Renin; D000254:Sodium-Potassium-Exchanging ATPase