Reduced ENaC protein abundance contributes to the lower blood pressure observed in pendrin-null mice.
Pendrin (encoded by Pds, Slc26a4) is a Cl(-)/HCO(3)(-) exchanger expressed in the apical regions of type B and non-A, non-B intercalated cells of kidney and mediates renal Cl(-) absorption, particularly when upregulated. Aldosterone increases blood pressure by increasing absorption of both Na(+) and Cl(-) through increased protein abundance and function of Na(+) transporters, such as the epithelial Na(+) channel (ENaC) and the Na(+)-Cl(-) cotransporter (NCC), as well as Cl(-) transporters, such as pendrin. Because aldosterone analogs do not increase blood pressure in Slc26a4(-/-) mice, we asked whether Na(+) excretion and Na(+) transporter protein abundance are altered in kidneys from these mutant mice. Thus wild-type and Slc26a4-null mice were given a NaCl-replete, a NaCl-restricted, or NaCl-replete diet and aldosterone or aldosterone analogs. Abundance of the major renal Na(+) transporters was examined with immunoblots and immunohistochemistry. Slc26a4-null mice showed an impaired ability to conserve Na(+) during dietary NaCl restriction. Under treatment conditions in which circulating aldosterone is increased, alpha-, beta-, and 85-kDa gamma-ENaC subunit protein abundances were reduced 15-35%, whereas abundance of the 70-kDa fragment of gamma-ENaC was reduced approximately 70% in Slc26a4-null relative to wild-type mice. Moreover, ENaC-dependent changes in transepithelial voltage were much lower in cortical collecting ducts from Slc26a4-null than from wild-type mice. Thus, in kidney, ENaC protein abundance and function are modulated by pendrin or through a pendrin-dependent downstream event. The reduced ENaC protein abundance and function observed in Slc26a4-null mice contribute to their lower blood pressure and reduced ability to conserve Na(+) during NaCl restriction.
Department of Medicine, Emory University, Atlanta, Georgia, USA.
Young Hee
YH
Kim
Vladimir
V
Pech
Kathryn B
KB
Spencer
William H
WH
Beierwaltes
Lorraine A
LA
Everett
Eric D
ED
Green
Wonkyong
W
Shin
Jill W
JW
Verlander
Roy L
RL
Sutliff
Susan M
SM
Wall
D000311:Adrenal Glands / Q000502:physiology; D000450:Aldosterone / Q000097:blood / Q000494:pharmacology; D000584:Amiloride / Q000494:pharmacology; D000818:Animals; D027321:Anion Transport Proteins / Q000235:genetics / Q000378:metabolism*; D001794:Blood Pressure / Q000502:physiology*; D003106:Colon / Q000378:metabolism; D053503:Epithelial Sodium Channels / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D005260:Female; D007031:Hypothalamus / Q000502:physiology; D007668:Kidney / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D012964:Sodium / Q000378:metabolism; D026941:Sodium Channel Blockers / Q000494:pharmacology; D049992:Sodium Chloride Symporters / Q000378:metabolism; D000076988:Sulfate Transporters; D013961:Thyroid Gland / Q000378:metabolism
D027321:Anion Transport Proteins; D053503:Epithelial Sodium Channels; C494849:Slc26a4 protein, mouse; D026941:Sodium Channel Blockers; D049992:Sodium Chloride Symporters; D000076988:Sulfate Transporters; D000450:Aldosterone; D000584:Amiloride; D012964:Sodium