MicroRNAs (miRNAs) are endogenous ∼23 nt RNAs that play important gene-regulatory roles in animals and plants by pairing to the mRNAs of protein-coding genes to direct their posttranscriptional repression. This review outlines the current understanding of miRNA target recognition in animals and discusses the widespread impact of miRNAs on both the expression and evolution of protein-coding genes.

MicroRNAs: Target Recognition and Regulatory Functions

Hormones regulating cardiovascular function in patients with severe congestive heart failure and their relation to mortality

-To study the effects of modestly increased expression of aldosterone synthase (AS), we generated mice (AS hi/hi ) by replacing the 3' untranslated region of AS mRNA with that from a stable mRNA. AS hi/hi mice on a normal-salt diet had 1.5 times the wild-type AS mRNA in adrenals, although their blood pressure and plasma aldosterone did not differ from wild-type mice. Changes in dietary salt did not affect the blood pressure of wild-type mice, but AS hi/hi mice had ≈10-mm Hg higher blood pressure on a high-salt diet than on a low-salt diet and than wild-type mice on either diet. The AS hi/hi mice on a high-salt diet also had higher plasma aldosterone, lower plasma potassium, and greater renal expression of the a subunit of epithelial sodium channel compared with wild-type mice. The AS hi/hi mice on a high-salt diet also had more water intake and urine volume and less urine osmolality than wild-type mice. On a low-salt diet, AS hi/hi mice maintained normal blood pressure with less activation of the renin-angiotensin-aldosterone system than wild-type mice. The AS hi/hi mice also had less water intake and urine volume and higher urine osmolality than wild-type mice. On a medium high-salt diet, AS hi/hi mice were more susceptible than wild-type mice to infusion of angiotensin II, having a higher blood pressure, greater cardiac hypertrophy, and increased oxidative stress. Thus, a modest increase in AS expression makes blood pressure more sensitive to salt, suggesting that genetically increased AS expression in humans may contribute to hypertension and cardiovascular complications in societies with high-salt diets.

Salt-Sensitive Blood Pressure in Mice With Increased Expression of Aldosterone Synthase. Commentary

Key points
Previous studies implicate nitric oxide (NO) in the control of sweating during exercise in the heat; however, it is unclear whether cyclooxygenase (COX) is also involved.
We demonstrated that exercise-induced sweating at a moderate heat production (400 W, ∼40% VO2 max ) was similarly reduced when COX and NO synthase were inhibited separately and in combination.
Alternatively, inhibiting COX and/or NO synthase did not influence exercise-induced sweating at a high heat production (700 W, ∼70% VO2 max ).
We show that both COX and NO are involved in sweating during exercise at moderate heat production and that the effects may not be independent. However, roles for COX and NO are less evident when heat production is elevated.
The results lead to better understanding of the mechanisms of sweating and indicate that COX inhibitors (e.g. aspirin) may impair core body temperature regulation and thereby increase the risk of heat-related illness.


Abstract
Our recent work implicated nitric oxide (NO) in the control of sweating during intermittent exercise; however, it is unclear if cyclooxygenase (COX) is also involved. On separate days, ten healthy young (24 ± 4 years) males cycled in the heat (35°C). Two 30 min exercise bouts were performed at either a moderate (400 W, moderate heat load) or high (700 W, high heat load) rate of metabolic heat production and were followed by 20 and 40 min of recovery, respectively. Forearm sweating (ventilated capsule) was evaluated at four skin sites that were continuously perfused via intradermal microdialysis with: (1) lactated Ringer solution (Control), (2) 10 mm ketorolac (a non-selective COX inhibitor), (3) 10 mm NG-nitro-l-arginine methyl ester (l-NAME; a non-selective NO synthase inhibitor) or (4) a combination of 10 mm ketorolac + 10 mm l-NAME. During the last 5 min of the first exercise at moderate heat load, forearm sweating (mg min−1 cm−2) was equivalently reduced with ketorolac (0.54 ± 0.08), l-NAME (0.55 ± 0.07) and ketorolac+l-NAME (0.56 ± 0.08) compared to Control (0.67 ± 0.06) (all P   0.05). We show that (1) although both COX and NO modulate forearm sweating during intermittent exercise bouts in the heat at a moderate heat load, the effects are not additive, and (2) the contribution of both enzymes to forearm sweating is less evident during intermittent exercise when the heat load is high and during recovery.

https://physoc.onlinelibrary.wiley.com/doi/pdf/10.1113/jphysiol.2014.280651

Evidence for cyclooxygenase‐dependent sweating in young males during intermittent exercise in the heat

cAMP stimulates cell proliferation and Cl(-)-dependent fluid secretion, promoting the progressive enlargement of renal cysts in autosomal dominant polycystic kidney disease (ADPKD). Intracellular cAMP levels are determined by the balance of cAMP synthesis by adenylyl cyclases and degradation by phosphodiesterases (PDEs). Therefore, PDE isoform expression and activity strongly influence global and compartmentalized cAMP levels. We report here that PDE3 and PDE4 expression levels are lower in human ADPKD tissue and cells compared with those of normal human kidneys (NHKs), whereas PDE1 levels are not significantly different. Inhibition of PDE4 caused a greater increase in basal and vasopressin (AVP)-stimulated cAMP levels and Cl(-) secretion by ADPKD cells than inhibition of PDE1, and inhibition of PDE4 induced cyst-like dilations in cultured mouse Pkd1(-/-) embryonic kidneys. In contrast, inhibition of PDE1 caused greater stimulation of extracellular signal-regulated kinase (ERK) and proliferation of ADPKD cells than inhibition of PDE4, and inhibition of PDE1 enhanced AVP-induced ERK activation. Notably, inhibition of PDE1, the only family of Ca(2+)-regulated PDEs, also induced a mitogenic response to AVP in NHK cells, similar to the effect of restricting intracellular Ca(2+). PDE1 coimmunoprecipitated with B-Raf and A-kinase anchoring protein 79, and AVP increased this interaction in ADPKD but not NHK cells. These data suggest that whereas PDE4 is the major PDE isoform involved in the regulation of global intracellular cAMP and Cl(-) secretion, PDE1 specifically affects the cAMP signal to the B-Raf/MEK/ERK pathway and regulates AVP-induced proliferation of ADPKD cells.

Phosphodiesterase Isoform Regulation of Cell Proliferation and Fluid Secretion in Autosomal Dominant Polycystic Kidney Disease

Arginine vasopressin (AVP) activates the epithelial Na+ channel (ENaC). The physiological significance of this activation is unknown. The present study tested if activation of ENaC contributes to AVP-sensitive urinary concentration. Consumption of a 3% NaCl solution induced hypernatremia and plasma hypertonicity in mice. Plasma AVP concentration and urine osmolality increased in hypernatremic mice in an attempt to compensate for increases in plasma tonicity. ENaC activity was elevated in mice that consumed 3% NaCl solution compared with mice that consumed a diet enriched in Na+ with ad libitum tap water; the latter diet does not cause hypernatremia. To determine whether the increase in ENaC activity in mice that consumed 3% NaCl solution served to compensate for hypernatremia, mice were treated with the ENaC inhibitor benzamil. Coadministration of benzamil with 3% NaCl solution decreased urinary osmolality and increased urine flow so that urinary Na+ excretion increased with no effect on urinary Na+ concentration. This decrease in urinary concentration further increased plasma Na+ concentration, osmolality, and AVP concentration in these already hypernatremic mice. Benzamil similarly compromised urinary concentration in water-deprived mice and in mice treated with desmopressin. These results demonstrate that stimulation of ENaC by AVP plays a critical role in water homeostasis by facilitating urinary concentration, which can compensate for hypernatremia or exacerbate hyponatremia. The present findings are consistent with ENaC in addition to serving as a final effector of the renin-angiotensin-aldosterone system and blood pressure homeostasis, also playing a key role in water homeostasis by regulating urine concentration and dilution of plasma.

Activation of ENaC by AVP contributes to the urinary concentrating mechanism and dilution of plasma

Under conditions of high dietary salt intake, prostaglandin E2 (PGE2) production is increased in the collecting duct and promotes urinary sodium chloride (NaCl) excretion; however, the molecular me...

https://www.physiology.org/doi/pdf/10.1152/ajpcell.00381.2012

Prostaglandin E2 induces chloride secretion through crosstalk between cAMP and calcium signaling in mouse inner medullary collecting duct cells

Micro-RNAs (miRNAs) are noncoding RNAs that bind target mRNA transcripts and modulate gene expression. In the cortical collecting duct (CCD), aldosterone stimulates the expression of genes that increase activity of the epithelial sodium channel (ENaC); in the early phase of aldosterone induction, one such gene is serum and glucocorticoid regulated kinase 1 (SGK1). We hypothesized that aldosterone regulates the expression of miRNAs in the early phase of induction to control the expression of target genes that stimulate ENaC activity. We treated mpkCCDc14 cells with aldosterone or vehicle for 1 h and used a miRNA microarray to analyze differential miRNA expression. We identified miR-466g as a miRNA that decreased by 57% after 1 h of aldosterone treatment. Moreover, we identified a putative miR-466g binding site in the 3'-untranslated region of SGK1. We constructed an SGK1 3'-untranslated region luciferase reporter and found that cotransfection of miR-466g suppressed luciferase activity in human embryonic kidney-293 cells in a dose-dependent manner. Deletion or introduction of point mutations that disrupt the miR-466g target site attenuated miR-466g-directed suppression of luciferase activity. Finally, we generated stably transduced mpkCCDc14 cell lines overexpressing miR-466g. Cells overexpressing miR-466g demonstrated 12.9-fold lower level of SGK1 mRNA compared with control cells after 6 h of aldosterone induction; moreover, cells overexpressing miR-466g exhibited 25% decrease in amiloride-sensitive current after 6 h of aldosterone induction and complete loss of amiloride-sensitive current after 24 h of aldosterone induction. Our findings implicate miR-466g as a novel early-phase aldosterone responsive miRNA that regulates SGK1 and ENaC in CCD cells.

SGK1 Regulation by miR-466g in Cortical Collecting Duct Cells.

inner medullary collecting duct cells crosstalk between cAMP and calcium signaling in mouse Prostaglandin E2 induces chloride secretion through

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Activation of ENaC by AVP contributes to the urinary concentrating mechanism and dilution of plasma

Prostaglandin E2 induces chloride secretion through crosstalk between cAMP and calcium signaling in mouse inner medullary collecting duct cells

SGK1 Regulation by miR-466g in Cortical Collecting Duct Cells.

inner medullary collecting duct cells crosstalk between cAMP and calcium signaling in mouse Prostaglandin E2 induces chloride secretion through