Aldosterone: Renal Action and Physiological Effects.

Aldosterone exerts profound effects on renal and cardiovascular physiology. In the kidney, aldosterone acts to preserve electrolyte and acid-base balance in response to changes in dietary sodium (Na ) or potassium (K ) intake. These physiological actions, principally through activation of mineralocorticoid receptors (MRs), have important effects particularly in patients with renal and cardiovascular disease as demonstrated by multiple clinical trials.

Knockout of the circadian clock protein PER1 results in sex-dependent alterations of ET-1 production in mice in response to a high-salt diet plus mineralocorticoid treatment.

Previously, we showed that global knockout (KO) of the circadian clock transcription factor PER1 in male, but not female, mice fed a high-salt diet plus mineralocorticoid treatment (HS/DOCP) resulted in nondipping hypertension and decreased night/day ratio of sodium (Na) excretion. Additionally, we have shown that the endothelin-1 (ET-1) gene is targeted by both PER1 and aldosterone. We hypothesized that ET-1 would exhibit a sex-specific response to HS/DOCP treatment in PER1 KO.

, A Novel Long Non-coding RNA Regulating Endothelin-1 in Human Proximal Tubule Cells.

Endothelin-1 (ET-1) is a peptide hormone that functions as a vasoconstrictor in the vasculature, whereas in the collecting duct of the kidney it exerts blood pressure-lowering effects via natriuretic actions. Aberrant ET-1 signaling is associated with several pathological states including hypertension and chronic kidney disease. ET-1 expression is regulated largely through transcriptional control of the gene that encodes ET-1, .

Female C57BL/6J mice lacking the circadian clock protein PER1 are protected from nondipping hypertension.

The circadian clock is integral to the maintenance of daily rhythms of many physiological outputs, including blood pressure. Our laboratory has previously demonstrated the importance of the clock protein period 1 (PER1) in blood pressure regulation in male mice. Briefly, a high-salt diet (HS; 4% NaCl) plus injection with the long-acting mineralocorticoid deoxycorticosterone pivalate (DOCP) resulted in nondipping hypertension [<10% difference between night and day blood pressure (BP) in Per1-knockout (KO) mice but not in wild-type (WT) mice].

Renal Na-handling defect associated with PER1-dependent nondipping hypertension in male mice.

Many physiological functions have a circadian rhythm, including blood pressure (BP). BP is highest during the active phase, whereas during the rest period, BP dips 10-20%. Patients that do not experience this dip at night are termed "nondippers.

Aldosterone alters the chromatin structure of the murine endothelin-1 gene.

Unlabelled: Aldosterone increases sodium reabsorption in the renal collecting duct and systemic blood pressure. Paradoxically, aldosterone also induces transcription of the endothelin-1 (Edn1) gene to increase protein (ET-1) levels, which inhibits sodium reabsorption.

Aims: Here we investigated changes in the chromatin structure of the Edn1 gene of collecting duct cell lines in response to aldosterone treatment.

Effect of mineralocorticoid treatment in mice with collecting duct-specific knockout of endothelin-1.

Aldosterone increases blood pressure (BP) by stimulating sodium (Na) reabsorption within the distal nephron and collecting duct (CD). Aldosterone also stimulates endothelin-1 (ET-1) production that acts within the CD to inhibit Na reabsorption via a negative feedback mechanism. We tested the hypothesis that this renal aldosterone-endothelin feedback system regulates electrolyte balance and BP by comparing the effect of a high-salt (NaCl) diet and mineralocorticoid stimulation in control and CD-specific ET-1 knockout (CD ET-1 KO) mice.

Tissue-specific and time-dependent regulation of the endothelin axis by the circadian clock protein Per1.

Aims: The present study is designed to consider a role for the circadian clock protein Per1 in the regulation of the endothelin axis in mouse kidney, lung, liver and heart. Renal endothelin-1 (ET-1) is a regulator of the epithelial sodium channel (ENaC) and blood pressure (BP), via activation of both endothelin receptors, ETA and ETB. However, ET-1 mediates many complex events in other tissues.

MicroRNA regulation of endothelin-1 mRNA in renal collecting duct cells.

Aims: Recently, microRNAs (miRNAs) have been implicated in control of Edn1 mRNA in several tissues. Here we examined the role of miRNA action on Edn1 mRNA expression in renal distal collecting duct cells.

Main Methods: A microarray study was conducted to provide a comprehensive assessment of miRNAs present in a murine inner medullary collecting duct (mIMCD-3) cell line.

Endothelin-1 inhibits sodium reabsorption by ET(A) and ET(B) receptors in the mouse cortical collecting duct.

The collecting duct (CD) is a major renal site for the hormonal regulation of Na homeostasis and is critical for systemic arterial blood pressure control. Our previous studies demonstrated that the endothelin-1 gene (edn1) is an early response gene to the action of aldosterone. Because aldosterone and endothelin-1 (ET-1) have opposing actions on Na reabsorption (JNa) in the kidney, we postulated that stimulation of ET-1 by aldosterone acts as a negative feedback mechanism, acting locally within the CD.

An emerging role for microRNA in the regulation of endothelin-1.

Endothelin-1 (ET-1) is a peptide signaling molecule serving diverse functions in many different tissues such as the vasculature and the kidney. The primary mechanism thought to control ET-1 bioavailability is the rate of transcription from the ET-1 gene (EDN1), but recent research suggests that EDN1 expression is attenuated by microRNA (miRNA)-mediated regulation. The action of specific miRNAs on EDN1 mRNA appears to vary greatly in a tissue specific manner.

The circadian protein period 1 contributes to blood pressure control and coordinately regulates renal sodium transport genes.

The circadian clock protein period 1 (Per1) contributes to the regulation of expression of the α subunit of the renal epithelial sodium channel at the basal level and in response to the mineralocorticoid hormone aldosterone. The goals of the present study were to define the role of Per1 in the regulation of additional renal sodium handling genes in cortical collecting duct cells and to evaluate blood pressure (BP) in mice lacking functional Per1. To determine whether Per1 regulates additional genes important in renal sodium handling, a candidate gene approach was used.

Dexamethasone stimulates endothelin-1 gene expression in renal collecting duct cells.

Aldosterone stimulates the endothelin-1 gene (Edn1) in renal collecting duct (CD) cells by a mechanism involving the mineralocorticoid receptor (MR) and the glucocorticoid receptor (GR). The goal of the present study was to determine if the synthetic glucocorticoid dexamethasone affected Edn1 gene expression and to characterize GR binding patterns to an element in the Edn1 promoter. Dexamethasone (1μM) induced a 4-fold increase in Edn1 mRNA in mIMCD-3 inner medullary CD cells.

Functional expression of human adenine nucleotide translocase 4 in Saccharomyces cerevisiae.

The adenine nucleotide translocase (ANT) mediates the exchange of ADP and ATP across the inner mitochondrial membrane. The human genome encodes multiple ANT isoforms that are expressed in a tissue-specific manner. Recently a novel germ cell-specific member of the ANT family, ANT4 (SLC25A31) was identified.

Two rotary motors in F-ATP synthase are elastically coupled by a flexible rotor and a stiff stator stalk.

ATP is synthesized by ATP synthase (F(O)F(1)-ATPase). Its rotary electromotor (F(O)) translocates protons (in some organisms sodium cations) and generates torque to drive the rotary chemical generator (F(1)). Elastic power transmission between F(O) and F(1) is essential for smoothing the cooperation of these stepping motors, thereby increasing their kinetic efficiency.

Manipulations in the peripheral stalk of the Saccharomyces cerevisiae F1F0-ATP synthase.

The Saccharomyces cerevisiae F(1)F(0)-ATP synthase peripheral stalk is composed of the OSCP, h, d, and b subunits. The b subunit has two membrane-spanning domains and a large hydrophilic domain that extends along one side of the enzyme to the top of F(1). In contrast, the Escherichia coli peripheral stalk has two identical b subunits, and subunits with substantially altered lengths can be incorporated into a functional F(1)F(0)-ATP synthase.

Mineralocorticoids stimulate the activity and expression of renal H+,K+-ATPases.

In the renal collecting duct, mineralocorticoids drive Na(+) reabsorption, K(+) secretion, and H(+) secretion through coordinated actions on apical and basolateral transporters. Whether mineralocorticoids act through H(+),K(+)-ATPases to maintain K(+) and acid-base homeostasis is unknown. Here, treatment of mice with the mineralocorticoid desoxycorticosterone pivalate (DOCP) resulted in weight gain, a decrease in blood [K(+)] and [Cl(-)], and an increase in blood [Na(+)] and [HCO(3)(-)].

Regulation of αENaC expression by the circadian clock protein Period 1 in mpkCCD(c14) cells.

The epithelial sodium channel (ENaC) mediates the fine-tuned regulation of external sodium (Na) balance. The circadian clock protein Period 1 (Per1) is an aldosterone-induced gene that regulates mRNA expression of the rate-limiting alpha subunit of ENaC (αENaC). In the present study, we examined the effect of Per1 on αENaC in the cortex, the site of greatest ENaC activity in the collecting duct, and examined the mechanism of Per1 action on αENaC.

Endothelin-1 gene regulation.

Over two decades of research have demonstrated that the peptide hormone endothelin-1 (ET-1) plays multiple, complex roles in cardiovascular, neural, pulmonary, reproductive, and renal physiology. Differential and tissue-specific production of ET-1 must be tightly regulated in order to preserve these biologically diverse actions. The primary mechanism thought to control ET-1 bioavailability is the rate of transcription from the ET-1 gene (edn1).

The renal H,K-ATPases.

Purpose Of Review: We integrate recent evidence that demonstrates the importance of the gastric (HKalpha1) and nongastric (HKalpha2)-containing hydrogen potassium adenosine triphosphatases (H,K-ATPases) on physiological function and their role in potassium (K), sodium (Na), and acid-base balance.

Recent Findings: Previous studies focused on the primary role of H,K-ATPases as a mechanism of K conservation during states of K deprivation. Both isoforms function in H secretion and K absorption in vivo during K deprivation, but recent findings show that these pumps also function in acid secretion in animals fed normal K-replete diets.

Pharmacological profiles of the murine gastric and colonic H,K-ATPases.

Background: The H,K-ATPase, consisting of α and ß subunits, belongs to the P-type ATPase family. There are two isoforms of the α subunit, HKα₁ and HKα₂ encoded by different genes. The ouabain-resistant gastric HKα₁-H,K-ATPase is Sch28080-sensitive.

The renal H+-K+-ATPases: physiology, regulation, and structure.

The H(+)-K(+)-ATPases are ion pumps that use the energy of ATP hydrolysis to transport protons (H(+)) in exchange for potassium ions (K(+)). These enzymes consist of a catalytic alpha-subunit and a regulatory beta-subunit. There are two catalytic subunits present in the kidney, the gastric or HKalpha(1) isoform and the colonic or HKalpha(2) isoform.

Aldosterone modulates steroid receptor binding to the endothelin-1 gene (edn1).

Aldosterone and endothelin-1 (ET-1) act on collecting duct cells of the kidney and are important regulators of renal sodium transport and cardiovascular physiology. We recently identified the ET-1 gene (edn1) as a novel aldosterone-induced transcript. However, aldosterone action on edn1 has not been characterized at the present time.

The circadian clock protein Period 1 regulates expression of the renal epithelial sodium channel in mice.

The mineralocorticoid aldosterone is a major regulator of sodium transport in target epithelia and contributes to the control of blood pressure and cardiac function. It specifically functions to increase renal absorption of sodium from tubular fluid via regulation of the alpha subunit of the epithelial sodium channel (alphaENaC). We previously used microarray technology to identify the immediate transcriptional targets of aldosterone in a mouse inner medullary collecting duct cell line and found that the transcript induced to the greatest extent was the circadian clock gene Period 1.

The b subunits in the peripheral stalk of F1F0 ATP synthase preferentially adopt an offset relationship.

The peripheral stalk of F1F0 ATP synthase is essential for the binding of F1 to FO and for proper transfer of energy between the two sectors of the enzyme. The peripheral stalk of Escherichia coli is composed of a dimer of identical b subunits. In contrast, photosynthetic organisms express two b-like genes that form a heterodimeric peripheral stalk.