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A Potential Role of Histone Methyltransferase, Dot1l, in Renal Regulation of Acid‐Base Balance
Author(s) -
Nakhoul Nazih,
ElDahr Samir,
Brown Karen,
Islam M Toriqul,
Khan Altaf,
HeringSmith Kathleen,
Hamm L.Lee,
AbdulnourNakhoul Solange
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.666.29
Subject(s) - microbiology and biotechnology , intercalated cell , histone h3 , biology , histone , chemistry , biochemistry , endocrinology , medicine , kidney , gene
The histone methyltransferase Dot1l is a key epigenetic factor that plays a critical role in embryogenesis, angiogenesis, expression of the collecting duct epithelial Na channel (ENaC)and possibly hypertension. Deletion of Dot1l from renal cells expressing AQP2 resulted in a phenotype whereby kidneys had fewer principal cells and more intercalated cells (IC). It was reported that Dot1l, forming a complex with Af9 (a DNA binding protein) mediated transcriptional repression of ENaC‐α. Because of this transcriptional effect we hypothesized that targeted deletion of Dot1l from the collecting duct may affect expression of other transporters in the collecting duct. To test this hypothesis, we crossed Hoxb7‐Cre to Dot1 F/F mice to generate collecting duct Dot1l knockout (Dot1l ‐/‐ ) mice. We then placed control (WT) and renal Dot1l ‐/‐ mice on acid diet for 3 days and examined the expression and distribution of Rhbg and Rhcg by immunohistochemistry and Western analysis. Rhbg and Rhcg are NH 3 /NH 4 + transporters located respectively at the basolateral and apical membranes of IC. In response to acid diet Dot1l ‐/‐ mice showed an increase in net NH 4 + excretion. Rhcg and Rhbg were abundantly expressed but there was no change in Rhcg among the different groups. Rhbg expression was similar in WT & Dot1l ‐/‐ under normal diet but was significantly increased in Dot1l ‐/‐ mice on acid diet. These data suggest that Dot1l pathways may play a role in affecting renal acid‐base transport. This may be due, at least in part, to the increased expression of Rhbg transporters in DOT1l ‐/‐ but a direct effect on transporter function is also possible. Supported by VA Merit Grant