The renal thiazide-sensitive Na-Cl cotransporter as mediator of the aldosterone-escape phenomenon

Xiao Yan Wang, Shyama Masilamani, Jakob Nielsen, Tae Hwan Kwon, Heddwen L. Brooks, Søren Nielsen, Mark A. Knepper

Research output: Contribution to journalArticlepeer-review

112 Scopus citations


The kidneys "escape" from the Na-retaining effects ofaldosterone when circulating levels of aldosterone are inappropriately elevated in the setting of normal or expanded extracellular fluid volume, e.g., in primary aldosteronism. Using a targeted proteomics approach, we screened renal protein extracts with rabbit polyclonal antibodies directed to each of the major Na transporters expressed along the nephron to determine whether escape from aldosterone-mediated Na retention is associated with decreased abundance of one or more of renal Na transporters. The analysis revealed that the renal abundance of the thiazide-sensitive Na-Cl cotransporter (NCC) was profoundly and selectively decreased. None of the other apical solute-coupled Na transporters displayed decreases in abundance, nor were the total abundances of the three ENaC subunits significantly altered. Immunocytochemistry showed a strong decrease in NCC labeling in distal convoluted tubules of aldosterone-escape rats with no change in the cellular distribution of NCC. Ribonuclease protection assays (RPAs) revealed that the decrease in NCC protein abundance was not associated with altered NCC mRNA abundance. Thus, the thiazide-sensitive Na-Cl cotransporter of the distal convoluted tubule appears to be the chief molecular target for regulatory processes responsible for mineralocorticoid escape, decreasing in abundance via a posttranscriptional mechanism.

Original languageEnglish (US)
Pages (from-to)215-222
Number of pages8
JournalJournal of Clinical Investigation
Issue number2
StatePublished - 2001

ASJC Scopus subject areas

  • Medicine(all)


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