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Aldosterone‐Induced MicroRNAs Act as Negative Feedback Regulators for the Mineralocorticoid Receptor in Kidney Distal Nephron Epithelia
Author(s) -
OzbakiYagan Nejla,
Liu Xiaoning,
Bodnar Andrew J,
Ho Jaqueline,
Butterworth Michael Bruce
Publication year - 2019
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.2019.33.1_supplement.862.26
Subject(s) - aldosterone , mineralocorticoid receptor , downregulation and upregulation , mineralocorticoid , microrna , endocrinology , medicine , biology , epithelial sodium channel , distal convoluted tubule , kidney , receptor , microbiology and biotechnology , nephron , chemistry , sodium , gene , biochemistry , organic chemistry
Regulated sodium (Na + ) homeostasis in the kidney is achieved by the action of the renin‐angiotensin‐aldosterone signaling cascade. The terminal signaling hormone, aldosterone binds to the mineralocorticoid receptor (MR) to increase Na + uptake across tubule epithelial cells by altering the expression and function of channels, transporters and regulatory proteins acting in concert. Along with a change in gene and protein expression, aldosterone regulates the expression of non‐coding RNAs including microRNAs (miRs). The primary function of miRs is to repress target mRNA expression and decrease protein abundance. Extended aldosterone stimulation (1–7 days) is known to reduce MR expression (protein and mRNA) in cell and animal models. To investigate if miRs were involved in this negative feedback regulation of the MR, we profiled the expression of miRs predicted to bind to the MR‐3’untranslated region (UTR) in mouse cortical collecting duct (mCCD) epithelial cells stimulated with aldosterone (50nM). Of the significantly altered miRs, the miR‐466a‐e family members were most highly upregulated (>5 fold). This upregulation was verified in vivo in CCD cells isolated from mouse kidneys of animals placed on low Na + diets for 3 days. Luciferase assays confirmed miR‐466 binding to the MR‐UTR. Preventing the upregulation of miR‐466 after aldosterone stimulation, using miR inhibitors increased MR protein expression. Aldosterone‐stimulated sodium transport via the epithelial sodium channel in miR‐466 inhibited CCD cells was significantly higher than control transfected cells. The Na + ‐stimulation was sustained over extended periods (24–72hrs) and miR‐466 inhibited cells had increased aldosterone sensitivity. In conclusion, we have identified a role for the miR‐466's in the negative feedback regulation of MR after extended aldosterone stimulation. Inhibition of miR‐466 released this feedback regulation to allow for a larger, more sensitive and more sustained response to aldosterone stimulation. Support or Funding Information NIDDK R01DK103776 (JH) NIDDK DK102843 (MB) This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .