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Aldosterone modulates the activity of both epithelial (specifically renal) and non-epithelial cells. Binding to the mineralocorticoid receptor (MR), activates two pathways: the classical genomic and the rapidly activated non-genomic that is substantially modulated by the level of striatin. We hypothesized that disruption of MR’s non-genomic pathway would alter aldosterone-induced cardiovascular/renal damage. To test this hypothesis, wild type (WT) and striatin heterozygous knockout (Strn+/−) littermate male mice were fed a liberal sodium (1.6% Na+) diet and randomized to either protocol one: 3 weeks of treatment with either vehicle or aldosterone plus/minus MR antagonists, eplerenone or esaxerenone or protocol two: 2 weeks of treatment with either vehicle or L-NAME/AngII plus/minus MR antagonists, spironolactone or esaxerenone. Compared to the WT mice, basally, the Strn+/− mice had greater (~26%) estimated renal glomeruli volume and reduced non-genomic second messenger signaling (pAkt/Akt ratio) in kidney tissue. In response to active treatment, the striatin-associated-cardiovascular/renal damage was limited to volume effects induced by aldosterone infusion: significantly increased blood pressure (BP) and albuminuria. In contrast, with aldosterone or L-NAME/AngII treatment, striatin deficiency did not modify aldosterone-mediated damage: in the heart and kidney, macrophage infiltration, and increases in aldosterone-induced biomarkers of injury. All changes were near-normalized following MR blockade with spironolactone or esaxerenone, except increased BP in the L-NAME/AngII model. In conclusion, the loss of striatin amplified aldosterone-induced damage suggesting that aldosterone’s non-genomic pathway is protective but only related to effects likely mediated via epithelial, but not non-epithelial cells.

LSD1 (lysine-specific demethylase-1) is an epigenetic regulator of gene transcription. LSD1 risk allele in humans and LSD1 deficiency ( LSD1 +/− ) in mice confer increasing salt-sensitivity of blood pressure with age, which evolves into salt-sensitive hypertension in older individuals. However, the mechanism underlying the relationship between LSD1 and salt-sensitivity of blood pressure remains elusive. Here, we show that LSD1 genotype (in humans) and LSD1 deficiency (in mice) lead to similar associations with increased blood pressure and urine potassium levels but with decreased aldosterone levels during a liberal salt diet. Thus, we hypothesized that LSD1 deficiency leads to an MR (mineralocorticoid receptor)-dependent hypertensive state. Yet, further studies in LSD1 +/− mice treated with the MR antagonist eplerenone demonstrate that hypertension, kaliuria, and albuminuria are substantially improved, suggesting that the ligand-independent activation of the MR is the underlying cause of this LSD1 deficiency–mediated phenotype. Indeed, while MR and epithelial sodium channel expression levels were increased in LSD1 +/− mouse kidney tissues, aldosterone secretion from LSD1 +/− glomerulosa cells was significantly lower. Collectively, these data establish that LSD1 deficiency leads to an inappropriate activation and increased levels of the MR during a liberal salt regimen and suggest that inhibiting the MR pathway is a useful strategy for treatment of hypertension in human LSD1 risk allele carriers.

Background: The Coronavirus disease 2019 (COVID-19) disease is a pandemic disease spread worldwide and results in lifestyle changes in areas affected by COVID-19. The ongoing social distancing and lockdowns may negatively impact access to medical care and management of type 2 diabetes mellitus (T2DM). Accordingly, we examined the impact of the COVID-19 virus pandemic in Thailand on the glycemic control of patients with T2DM. Method: This study focused on T2DM outpatients at Rajavithi Hospital. Three hundred and fifty participants were included. Baseline characteristics, data on exercise, outdoor activities, and access to foods and blood chemistries, including hemoglobin A1C (A1C) and fasting plasma glucose (FPG), were reviewed, and collected from electronic medical records before and after the COVID-19 pandemic. Results: There was a significant increase in mean A1C (g/L) ± SD (74.8 ± 13.7 vs. 76.0 ± 15.3, p-value Conclusion: The present study showed that mean A1C was significantly increased during the COVID-19 virus pandemic. Nevertheless, a statistical difference was not observed in FPG. The impact of quarantine, social distancing, and community containment during the epidemic on lifestyles may be the essential factor in increasing A1C.

There are pros and cons of using fasting plasma glucose (FPG) and A1c for the diagnosis and management of diabetes. Still, discordance between FPG and A1c is a common problem in clinical practice, and there are no definite international guidelines for dealing with it. This article explains the causes of these anomalies and the factors that affect the results of tests, and it also recommends some appropriate techniques for investigation and management of cases of discordance between FPG and A1c.

Background : The β2-adrenergic receptor (β2-AR) has been implicated in blood pressure (BP) homeostasis via its effects on the sympathetic nervous system, cardiac function, peripheral vascular resistance, and renin release. We also have documented that a β2-AR diplotype (Arg16/Gln27), carried by 15% of hypertensives, have salt sensitive hypertension (SSBP) and increased aldosterone (ALDO). Gap in knowledge: it has been reported that hypertensive men and women respond differently to beta blockers. However, information regarding sex differences in carriers of the β2-AR risk diplotype is limited. Hypothesis : In mice, the phenotype in female carriers of the mutant β2-AR risk diplotype will differ from male carriers. Methods: The CRISPR/Cas9 approach was used to generate transgenic mice carrying 0, 1 or 2 Arg16/Gln27 variant alleles (i.e. wild-type (WT), heterozygous (Het) or mutant (Mut)). The experimental design included twelve weeks old mice divided into 6 genotype/gender groups (male and female; WT, Het and Mut) maintained on low (0.03% Na+, LS) and high sodium diets (1.6% Na+, HS) for a week each. Results: 1) Both male and female mice displayed significantly increased BP on LS and HS with increasing number of mutated alleles. 2) Only Mut females displayed SSBP (P 3) As compared to WT, urine and plasma ALDO levels were lower in male (but not female) carriers of the mutated allele (P 4) As anticipated, urine K+ excretion was significantly lower in the Mut male (but not female) mice (P 5) Doppler ultrasound measurements of renovascular function shows that the resistive index was significantly lower in Mut vs WT males (P 6) β2-AR expression was significantly lower in female vs. male WT mice; however, this difference was lost in the carriers of the mutated allele, as B2-AR expression levels were significantly higher in female carriers of the mutated allele, as compared to WT (P Conclusion: Both male and female Mut animals have increased BP compared to WT mice, but the mechanisms underlying their increased BP differ by sex. Female Mut mice have SSBP, inappropriately non-suppressed ALDO and decreased RBF. Male Mut mice do not have SSBP and have appropriate ALDO and RBF response to the salt load.

The mechanistic target of the rapamycin (mTOR) pathway plays a role in features common to both excess salt/aldosterone and cardiovascular/renal diseases. Dietary sodium can upregulate mTORC1 signaling in cardiac and renal tissue, and the inhibition of mTOR can prevent aldosterone-associated, salt-induced hypertension. The impact of sex and age on mTOR’s role in volume homeostasis and the regulation of aldosterone secretion is largely unknown. We hypothesize that both age and sex modify mTOR’s interaction with volume homeostatic mechanisms. The activity of 3 volume homeostatic mechanisms—cardiovascular, renal, and hormonal (aldosterone [sodium retaining] and brain natriuretic peptide [BNP; sodium losing])—were assessed in mTORC1 deficient (Raptor +/-) and wild-type male and female littermates at 2 different ages. The mice were volume stressed by being given a liberal salt (LibS) diet. Raptor +/-mice of both sexes when they aged: (1) reduced their blood pressure, (2) increased left ventricular internal diameter during diastole, (3) decreased renal blood flow, and (4) increased mineralocorticoid receptor expression. Aldosterone levels did not differ by sex in young Raptor +/- mice. However, as they aged, compared to their littermates, aldosterone decreased in males but increased in females. Finally, given the level of Na+ intake, BNP was inappropriately suppressed, but only in Raptor +/- males. These data indicate that Raptor +/- mice, when stressed with a LibS diet, display inappropriate volume homeostatic responses, particularly with aging, and the mechanisms altered, differing by sex.

The beta-2 adrenergic receptor (B2AR) is an established regulator of vascular tone and cardiac contractility. Two polymorphisms of the B2AR (Gly16Arg and Glu27Gln) have been associated with cardiovascular phenotypes, including hypertension, salt sensitivity of BP, cardiovascular disease and responses to antihypertensives. These same variants are associated with changes in receptor downregulation and desensitization in pulmonary tissues; however, there is no information on the effect of these polymorphisms on B2AR expression/function in cardiovascular tissues. To investigate the effect of these variants on cardiovascular function, we used the CRISPR/Cas9 approach to generate transgenic mice that carry the diplotype Arg16/Gln27 on 2, 1 or 0 alleles, i. e. mutant (Mut), heterozygous (Het) and wild-type (WT). Both male and female mice displayed significantly higher body weights with the increase in number of mutated alleles (P

Background: Measurements of thyrotropin (TSH), total and free thyroxine (TT4,FT4), triiodothyronine (TT3,FT3) are widely used diagnostic methods for thyroid function evaluation. However, some serum samples demonstrate a nonspecific binding with assay reagents that can interfere with the measurement of these hormones. Several steps can be taken to identify results that may reflect the presence of interfering factors including: 1) discrepancies between current values and previous results using the same methods; 2) clues from the clinical setting; 3) the pattern of discrepant and non-discrepant thyroid profile results (1,2) Clinical case: A 67-year-old woman admitted with generalized muscle weakness for one week. On physical examination she had left facial palsy (LMN), dysarthria, motor power grade 1 in her lower extremities and grade 3 in her upper extremities, her deep tendon reflex was diminished and her peripheral sensation was decreased as glove and stocking pattern. She was also experiencing normal anal sphincter tone and perianal sensation. She was diagnosed with hypertension and she was prescribed atenolol for treatment. She was clinically euthyroid. Provisional clinical diagnosis was Guillain-Barre syndrome. Because her laboratory profile showed hyponatremia, the following thyroid function tests were ordered: TSH 7.090 mIU/L (0.27-4.20 normal range [NR]); FT3 13.33 pg/ml (2.00-4.40 NR); FT4 1.37 ng/dl (0.93-1.70 NR) tested by one-step electrochemiluminescent immunoassay (ECLIA,Roche platform,Cobas®);anti-thyroid peroxidase antibody (16.25 IU/ml, normal); anti-thyroglobulin antibody (

Lysine-specific demethylase-1 (LSD1) is a histone demethylase that mediates epigenetic regulation of gene transcription. We have shown that human risk allele carriers of a LSD1 variant as well as a LSD1 heterozygous knockout mice (LSD1+/-) have salt sensitive hypertension (HTN), but low aldosterone (ALDO) and plasma renin activity (PRA) levels. However, in young mice ALDO levels are inappropriately increased for the level of salt intake. Thus, we hypothesize that despite the low ALDO levels, the salt sensitive HTN is mineralocorticoid mediated secondary to an overactive mineralocorticoid receptor(MR). To test our hypothesis, wild-type (LSD1+/+) and LSD1+/- mice were fed a liberal sodium (1.6% Na+) diet for 7 days and were then randomized to placebo or eplerenone (Epl) treatment for 2 weeks. Systolic blood pressures (SBP) were measured before and after the intervention; albumin/creatinine ratios (A/C), plasma ALDO, as well as urine ALDO, sodium and potassium were measured at the end of the study. Results: Compared with LSD1+/+, LSD1+/- mice displayed higher SBP at the beginning of the study (132 ± 2.6 mmHg vs 113.8 ± 2.0 mmHg; P