MicroRNA-132 controls water homeostasis through regulating MECP2-mediated vasopressin synthesis

Abstract

Fine-tuning of the body's water balance is regulated by vasopressin (AVP), which induces the expression and apical membrane insertion of aquaporin-2 water channels and subsequent water reabsorption in the kidney. Here we demonstrate that silencing of microRNA-132 (miR-132) in mice causes severe weight loss due to acute diuresis coinciding with increased plasma osmolality, reduced renal total and plasma membrane expression of aquaporin-2, and abrogated increase in AVP levels. Infusion with synthetic AVP fully reversed the antagomir-132-induced diuresis, and low-dose intracerebroventricular administration of antagomir-132 similarly caused acute diuresis. Central and intracerebroventricular antagomir-132 injection both decreased hypothalamic AVP mRNA levels. At the molecular level, antagomir-132 increased the in vivo and in vitro mRNA expression of methyl-CpG-binding protein-2 (MECP2), which is a miR-132 target and which blocks AVP gene expression by binding its enhancer region. In line with this, treatment of hypothalamic N6 cells with a high-salt solution increased its miR-132 levels, whereas it attenuated endogenous Mecp2 mRNA levels. In conclusion, we identified miR-132 as a first miRNA regulating the osmotic balance by regulating the hypothalamic AVP gene mRNA expression.

Vasopressin–aquaporin-2 pathway: recent advances in understanding water balance disorders

“…The possibility of using miRNA alone or in combination with other drugs to modulate the vasopressin–AQP2 pathway specifically provides new hints for AQP-based therapeutics 27, 123 . In this respect, the recent identification of miR-132 as a first miRNA target which blocks vasopressin gene expression has opened new avenues for drug development 124 .…”

New insights into the transcriptional regulation of aquaporin-2 and the treatment of X-linked hereditary nephrogenic diabetes insipidus

“…In addition, microR-NAs (miRNA; e.g., miR-32 and miR-137) are important post-transcriptional modulators that regulate AQP2 protein abundance [53,54]. A recent study showed that miR-132 regulates hypothalamic AVP mRNA expression [55]. Methyl-CpG-binding protein-2 is a target of miR-132 that inhibits hypothalamic AVP synthesis by binding the methyl-CpG-binding protein-2 enhancer region [55].…”

“…A recent study showed that miR-132 regulates hypothalamic AVP mRNA expression [55]. Methyl-CpG-binding protein-2 is a target of miR-132 that inhibits hypothalamic AVP synthesis by binding the methyl-CpG-binding protein-2 enhancer region [55].…”

Writers and Readers of DNA Methylation/Hydroxymethylation in Physiological Aging and Its Impact on Cognitive Function

“…This evidence suggests a relevant role for Mecp2 in aging that has not been explored and remains a key piece of information to understand the role of epigenetic mediators in the aging-associated cognitive decline. Furthermore, the evidence suggests that Mecp2 is target to miRNAs [63, 64] and the MECP2 gene contains a CpG island that could be associated with its transcriptional control [65]; however, such mechanism for the regulation of Mecp2 expression in aging has not been explored.…”