| First Author | Zhang X | Year | 2013 |
| Journal | Am J Physiol Renal Physiol | Volume | 305 |
| Issue | 10 | Pages | F1436-44 |
| PubMed ID | 24026182 | Mgi Jnum | J:202992 |
| Mgi Id | MGI:5523739 | Doi | 10.1152/ajprenal.00202.2013 |
| Citation | Zhang X, et al. (2013) Mineralocorticoid receptor antagonizes Dot1a-Af9 complex to increase alphaENaC transcription. Am J Physiol Renal Physiol 305(10):F1436-44 |
| abstractText | Aldosterone is a major regulator of Na(+) absorption and acts by activating the mineralocorticoid receptor (MR) to stimulate the epithelial Na(+) channel (ENaC). MR(-/-) mice exhibited pseudohypoaldosteronism type 1 (hyponatremia, hyperkalemia, salt wasting, and high levels of aldosterone) and died around postnatal day 10. However, if and how MR regulates ENaC transcription remain incompletely understood. Our earlier work demonstrated that aldosterone activates alphaENaC transcription by reducing expression of Dot1a and Af9 and by impairing Dot1a-Af9 interaction. Most recently, we reported identification of a major Af9 binding site in the alphaENaC promoter and upregulation of alphaENaC mRNA expression in mouse kidneys lacking Dot1a. Despite these findings, the putative antagonism between the MR/aldosterone and Dot1a-Af9 complexes has never been addressed. The molecular defects leading to PHA-1 in MR(-/-) mice remain elusive. Here, we report that MR competes with Dot1a to bind Af9. MR/aldosterone and Dot1a-Af9 complexes mutually counterbalance ENaC mRNA expression in inner medullary collecting duct 3 (IMCD3) cells. Real-time RT-quantitative PCR revealed that 5-day-old MR(-/-) vs. MR(+/+) mice had significantly lower alphaENaC mRNA levels. This change was associated with an increased Af9 binding and H3 K79 hypermethylation in the alphaENaC promoter. Therefore, this study identified MR as a novel binding partner and regulator of Af9 and a novel mechanism coupling MR-mediated activation with relief of Dot1a-Af9-mediated repression via MR-Af9 interaction. Impaired ENaC expression due to failure to inhibit Dot1a-Af9 may play an important role in the early stages of PHA-1 (before postnatal day 8) in MR(-/-) mice. |
