TY - JOUR
T1 - Direct and indirect mineralocorticoid effects determine distal salt transport
AU - Terker, Andrew S.
AU - Yarbrough, Bethzaida
AU - Ferdaus, Mohammed Z.
AU - Lazelle, Rebecca A.
AU - Erspamer, Kayla J.
AU - Meermeier, Nicholas P.
AU - Park, Hae J.
AU - McCormick, James A.
AU - Yang, Chao Ling
AU - Ellison, David H.
N1 - Publisher Copyright:
Copyright © 2016 by the American Society of Nephrology.
PY - 2016
Y1 - 2016
N2 - Excess aldosterone is an important contributor to hypertension and cardiovascular disease. Conversely, low circulating aldosterone causes salt wasting and hypotension. Aldosterone activatesmineralocorticoid receptors (MRS) to increase epithelial sodium channel (ENaC) activity. However, aldosterone may also stimulate the thiazide-sensitive Na+-Cl2 cotransporter (NCC). Here, we generated mice in which MRS could be deleted along the nephron to test this hypothesis. These kidney-specific MR-knockout mice exhibited salt wasting, low BP, and hyperkalemia. Notably, we found evidence of deficient apical orientation and cleavage of ENaC, despite the salt wasting. Although these mice also exhibited deficient NCC activity, NCC could be stimulated by restricting dietary potassium, which also returned BP to control levels. Together, these results indicate that MRS regulate ENaC directly, but modulation of NCC is mediated by secondary changes in plasma potassium concentration. Electrolyte balance and BP seem to be determined, therefore, by a delicate interplay between direct and indirectmineralocorticoid actions in the distal nephron.
AB - Excess aldosterone is an important contributor to hypertension and cardiovascular disease. Conversely, low circulating aldosterone causes salt wasting and hypotension. Aldosterone activatesmineralocorticoid receptors (MRS) to increase epithelial sodium channel (ENaC) activity. However, aldosterone may also stimulate the thiazide-sensitive Na+-Cl2 cotransporter (NCC). Here, we generated mice in which MRS could be deleted along the nephron to test this hypothesis. These kidney-specific MR-knockout mice exhibited salt wasting, low BP, and hyperkalemia. Notably, we found evidence of deficient apical orientation and cleavage of ENaC, despite the salt wasting. Although these mice also exhibited deficient NCC activity, NCC could be stimulated by restricting dietary potassium, which also returned BP to control levels. Together, these results indicate that MRS regulate ENaC directly, but modulation of NCC is mediated by secondary changes in plasma potassium concentration. Electrolyte balance and BP seem to be determined, therefore, by a delicate interplay between direct and indirectmineralocorticoid actions in the distal nephron.
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U2 - 10.1681/ASN.2015070815
DO - 10.1681/ASN.2015070815
M3 - Article
C2 - 26712527
AN - SCOPUS:85021433641
SN - 1046-6673
VL - 27
SP - 2436
EP - 2445
JO - Journal of the American Society of Nephrology
JF - Journal of the American Society of Nephrology
IS - 8
ER -