Direct and indirect mineralocorticoid effects determine distal salt transport

Andrew S. Terker, Bethzaida Yarbrough, Mohammed Z. Ferdaus, Rebecca A. Lazelle, Kayla J. Erspamer, Nicholas P. Meermeier, Hae J. Park, James (Jim) McCormick, Chao-Ling Yang, David Ellison

Research output: Contribution to journalArticle

38 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)2436-2445
Number of pages10
JournalJournal of the American Society of Nephrology
Volume27
Issue number8
DOIs
StatePublished - 2016

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Mineralocorticoids
Aldosterone
Salts
Nephrons
Dietary Potassium
Epithelial Sodium Channels
Thiazides
Mineralocorticoid Receptors
Hyperkalemia
Water-Electrolyte Balance
Knockout Mice
Hypotension
Potassium
Cardiovascular Diseases
Hypertension
Kidney

ASJC Scopus subject areas

  • Nephrology

Cite this

Terker, A. S., Yarbrough, B., Ferdaus, M. Z., Lazelle, R. A., Erspamer, K. J., Meermeier, N. P., ... Ellison, D. (2016). Direct and indirect mineralocorticoid effects determine distal salt transport. Journal of the American Society of Nephrology, 27(8), 2436-2445. https://doi.org/10.1681/ASN.2015070815

Direct and indirect mineralocorticoid effects determine distal salt transport. / Terker, Andrew S.; Yarbrough, Bethzaida; Ferdaus, Mohammed Z.; Lazelle, Rebecca A.; Erspamer, Kayla J.; Meermeier, Nicholas P.; Park, Hae J.; McCormick, James (Jim); Yang, Chao-Ling; Ellison, David.

In: Journal of the American Society of Nephrology, Vol. 27, No. 8, 2016, p. 2436-2445.

Research output: Contribution to journalArticle

Terker, AS, Yarbrough, B, Ferdaus, MZ, Lazelle, RA, Erspamer, KJ, Meermeier, NP, Park, HJ, McCormick, JJ, Yang, C-L & Ellison, D 2016, 'Direct and indirect mineralocorticoid effects determine distal salt transport', Journal of the American Society of Nephrology, vol. 27, no. 8, pp. 2436-2445. https://doi.org/10.1681/ASN.2015070815
Terker AS, Yarbrough B, Ferdaus MZ, Lazelle RA, Erspamer KJ, Meermeier NP et al. Direct and indirect mineralocorticoid effects determine distal salt transport. Journal of the American Society of Nephrology. 2016;27(8):2436-2445. https://doi.org/10.1681/ASN.2015070815
Terker, Andrew S. ; Yarbrough, Bethzaida ; Ferdaus, Mohammed Z. ; Lazelle, Rebecca A. ; Erspamer, Kayla J. ; Meermeier, Nicholas P. ; Park, Hae J. ; McCormick, James (Jim) ; Yang, Chao-Ling ; Ellison, David. / Direct and indirect mineralocorticoid effects determine distal salt transport. In: Journal of the American Society of Nephrology. 2016 ; Vol. 27, No. 8. pp. 2436-2445.
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