ABSTRACT
The epithelial sodium channel (ENaC) is expressed in the epithelial cells of the distal convoluted tubules, connecting tubules, and cortical collecting duct (CCD) in the kidney nephron. Under the regulation of the steroid hormone aldosterone, ENaC is a major determinant of sodium (Na+ ) and water balance. The ability of aldosterone to regulate microRNAs (miRs) in the kidney has recently been realized, but the role of miRs in Na+ regulation has not been well established. Here we demonstrate that expression of a miR cluster mmu-miR-23-24-27, is upregulated in the CCD by aldosterone stimulation both in vitro and in vivo. Increasing the expression of these miRs increased Na+ transport in the absence of aldosterone stimulation. Potential miR targets were evaluated and miR-27a/b was verified to bind to the 3'-untranslated region of intersectin-2, a multi-domain protein expressed in the distal kidney nephron and involved in the regulation of membrane trafficking. Expression of Itsn2 mRNA and protein was decreased after aldosterone stimulation. Depletion of Itsn2 expression, mimicking aldosterone regulation, increased ENaC-mediated Na+ transport, while Itsn2 overexpression reduced ENaC's function. These findings reinforce a role for miRs in aldosterone regulation of Na+ transport, and implicate miR-27 in aldosterone's action via a novel target. J. Cell. Physiol. 232: 1306-1317, 2017. © 2016 Wiley Periodicals, Inc.
Subject(s)
Aldosterone/pharmacology , MicroRNAs/metabolism , Nephrons/metabolism , Sodium/metabolism , Up-Regulation/drug effects , 3' Untranslated Regions/genetics , Adaptor Proteins, Vesicular Transport/metabolism , Animals , Biological Transport/drug effects , Epithelial Cells/drug effects , Epithelial Cells/metabolism , Epithelial Sodium Channels/metabolism , Kidney Tubules, Collecting/drug effects , Kidney Tubules, Collecting/metabolism , Mice, Inbred C57BL , MicroRNAs/genetics , Nephrons/drug effects , Protein Binding/drug effects , RNA, Messenger/genetics , RNA, Messenger/metabolism , Ribonuclease III/metabolism , Signal Transduction/drug effectsABSTRACT
PURPOSE OF REVIEW: Renal dysplasia is classically described as a developmental disorder whereby the kidneys fail to undergo appropriate differentiation, resulting in the presence of malformed renal tissue elements. It is the commonest cause of chronic kidney disease and renal failure in the neonate. Although several genes have been identified in association with renal dysplasia, the underlying molecular mechanisms are often complex and heterogeneous in nature, and remain poorly understood. RECENT FINDINGS: In this review, we describe new insights into the fundamental process of normal kidney development, and how the renal cortex and medulla are patterned appropriately during gestation. We review the key genes that are indispensable for this process, and discuss how patterning of the kidney is perturbed in the absence of these signaling pathways. The recent use of whole exome sequencing has identified genetic mutations in patients with renal dysplasia, and the results of these studies have increased our understanding of the pathophysiology of renal dysplasia. SUMMARY: At present, there are no specific treatments available for patients with renal dysplasia. Understanding the molecular mechanisms of normal kidney development and the pathogenesis of renal dysplasia may allow for improved therapeutic options for these patients.
