Regulation of epithelial sodium transport by promyelocytic leukemia zinc finger protein.
Aldosterone is the principal regulator of Na homeostasis, and thereby blood pressure. One of the main targets of aldosterone is the epithelial Na channel (ENaC) located in the apical membrane of target cells. Previous studies identified several genes involved in the regulation of ENaC such as SGK1; however, SGK1 knockout mice have only a mild salt-losing phenotype, indicating that further genes must be involved in the action of aldosterone. In our search for further aldosterone-regulated genes, we discovered that aldosterone, at physiological concentrations, induces the expression of the promyelocytic leukemia zinc finger protein (PLZF) in renal cortical collecting duct (CCD) cell lines that stably express mineralocorticoid receptors (MRs). This effect is rapid and does not require de novo protein synthesis, suggesting a direct action. Surprisingly, stable overexpression of human or mouse PLZF isoforms significantly decreased transepithelial Na transport in CCD cells while having no effect on the integrity of the monolayers. In parallel with the decline in Na transport, PLZF suppressed the mRNA levels of beta- and gamma-ENaC subunits. These observations suggest that PLZF is a negative regulator of ENaC in renal epithelial cells and might be part of a negative feedback loop that limits aldosterone's stimulatory effects on sodium reabsorption.
Náray-Fejes-Tóth
Anikó
A
Department of Physiology, Dartmouth Medical School, Lebanon, NH 03756-0001, USA. aniko.fejes-toth@dartmouth.edu
Boyd
Cary
C
Fejes-Tóth
Géza
G
D000450:Aldosterone / Q000502:physiology*; D000818:Animals; D004318:Doxycycline / Q000494:pharmacology; D053503:Epithelial Sodium Channels / Q000187:drug effects / Q000502:physiology*; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000502:physiology*; D051379:Mice; D000075722:Promyelocytic Leukemia Zinc Finger Protein; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D016335:Zinc Fingers / Q000502:physiology; D050880:p300-CBP Transcription Factors / Q000037:antagonists & inhibitors; D000099224:p300-CBP-Associated Factor
D000450:Aldosterone; D004318:Doxycycline; D053503:Epithelial Sodium Channels; D056572:Histone Deacetylase Inhibitors; D051741:Kruppel-Like Transcription Factors; D000075722:Promyelocytic Leukemia Zinc Finger Protein; D012333:RNA, Messenger; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor; C092037:ZBTB16 protein, human