Aldosterone‐induced microRNAs act as feedback regulators of mineralocorticoid receptor signaling in kidney epithelia

Abstract

The final steps in the Renin‐Angiotensin‐Aldosterone signaling System (RAAS) involve binding of the corticosteroid hormone, aldosterone to its mineralocorticoid receptor (MR). The bound MR interacts with response elements to induce or repress the transcription of aldosterone‐regulated genes. A well characterized aldosterone‐induced gene is the serum and glucocorticoid‐induced kinase (SGK1), which acts downstream to increase sodium transport in distal kidney nephron epithelial cells. The role of microRNAs (miRs) induced by extended aldosterone stimulation in regulating MR and SGK1 has not been reported. In these studies, miRs predicted to bind to the 3ʹ‐UTR of mouse MR were profiled by qRT‐PCR after aldosterone stimulation. The miR‐466a/b/c/e family was upregulated in mouse kidney cortical collecting duct epithelial cells. A luciferase reporter assay confirmed miR‐466 binding to both MR and SGK1 3ʹ‐UTRs. Inhibition of miR‐466 increased MR and SGK1 mRNA and protein levels. Inhibiting miR‐466b and preventing its upregulation after aldosterone stimulation increased amiloride‐sensitive sodium transport and sensitivity to aldosterone stimulation. In vivo upregulation of miR‐466 was confirmed in distal nephrons of mice on low Na+ diets. Repression of MR and SGK1 by aldosterone‐induced miRs may represent a negative feedback loop that contributes to a form of aldosterone escape in vivo.

Importance of Micromilieu for Pathophysiologic Mineralocorticoid Receptor Activity—When the Mineralocorticoid Receptor Resides in the Wrong Neighborhood

“…For example, the miR-466 family, consisting of mir-466a, miR-466b, miR-466c, and miR-466e, not only negatively regulates the expression of the MR, but also the expression of one of its well-known target genes, SGK1. It could be shown that the expression of the miR-466 family is induced by aldosterone in the collecting duct, suggesting a negative feedback loop [ 171 ]. While some of the miRs seem to be part of negative feedback loops in MR regulation, there is also evidence that, under pathologic conditions, the expression of MR regulating miRs decreases.…”

Role of microRNAs in Obesity-Related Kidney Disease

“…RAAS is essential for the management of renal salt, water conservation, and blood pressure [ 32 ]. Importantly, changes in miRNAs expression have been shown to have an influence on the components of the RAAS pathway [ 33 ]. miR-466a/b/c/e family has been shown to be regulated by aldosterone (ALDO) and contributes to a negative feedback loop that reduces long-term ALDO signaling.…”

“…miR-466a/b/c/e family has been shown to be regulated by aldosterone (ALDO) and contributes to a negative feedback loop that reduces long-term ALDO signaling. Thus, the miR-466a/b/c/e family protects aldosterone-sensitive tissues from excessive ALDO exposure [ 33 ] and plays an important role in kidney homeostasis. Furthermore, miR-6869-5p has also been described as a regulator of the RAAS cascade [ 34 ].…”

Sexual Dimorphism of Corticosteroid Signaling during Kidney Development

“…On the opposite, MR transcript levels increase under hypotonicity thanks to the recruitment of Human antigen R (HuR), another RBP, which interacts with MR 3′-UTR in the cytoplasm of renal cells to stabilize and increase MR levels, thereby modulating MR signaling [ 24 ]. Accumulating evidence now underscores the pivotal role of microRNAs (miRNAs), an additional class of post-transcriptional regulators, in the control of MR expression in the kidney [ 25 , 26 ]. Beyond these regulatory mechanisms, MR activity and signaling are also modulated by post-translational modifications such as ubiquitylation, SUMOylation, phosphorylation, and acetylation [ 13 , 27 ].…”