Selective Deletion of the Mechanistic Target of Rapamycin From the Renal Collecting Duct Principal Cell in Mice Down-Regulates the Epithelial Sodium Channel

The mechanistic target of rapamycin (mTOR), a serine-threonine-specific kinase, is a cellular energy sensor, integrating growth factor and nutrient signaling. In the collecting duct (CD) of the kidney, the epithelial sodium channel (ENaC) essential in the determination of final urine Na+ losses, has been demonstrated to be upregulated by mTOR, using cell culture and mTOR inhibition in ex vivo preparations. We tested whether CD-principal cell (PC) targeted deletion of mTOR using Cre-lox recombination would affect whole-body sodium homeostasis, blood pressure, and ENaC regulation in mice. Male and female CD-PC mTOR knockout (KO) mice and wild-type (WT) littermates (Cre-negative) were generated using aquaporin-2 (AQP2) promoter to drive Cre-recombinase. Under basal conditions, KO mice showed a reduced (∼30%) natriuretic response to benzamil (ENaC) antagonist, suggesting reduced in vivo ENaC activity. WT and KO mice were fed normal sodium (NS, 0.45% Na+) or a very low Na+ (LS, <0.02%) diet for 7-days. Switching from NS to LS resulted in significantly higher urine sodium losses (relative to WT) in the KO with adaptation occurring by day 2. Blood pressures were modestly (∼5–10 mm Hg) but significantly lower in KO mice under both diets. Western blotting showed KO mice had 20–40% reduced protein levels of all three subunits of ENaC under LS or NS diet. Immunohistochemistry (IHC) of kidney showed enhanced apical-vs.-cellular localization of all three subunits with LS, but a reduction in this ratio for γ-ENaC in the KO. Furthermore, the KO kidneys showed increased ubiquitination of α-ENaC and reduced phosphorylation of the serum and glucocorticoid regulated kinase, type 1 [serum glucocorticoid regulated kinase (SGK1)] on serine 422 (mTOR phosphorylation site). Taken together this suggests enhanced degradation as a consequence of reduced mTOR kinase activity and downstream upregulation of ubiquitination may have accounted for the reduction at least in α-ENaC. Overall, our data support a role for mTOR in ENaC activity likely via regulation of SGK1, ubiquitination, ENaC channel turnover and apical membrane residency. These data support a role for mTOR in the collecting duct in the maintenance of body sodium homeostasis.

Associations of Serum Uromodulin and Its Genetic Variants With Blood Pressure and Hypertension in Chinese Adults

Background: Uromodulin, also named Tamm Horsfall protein, has been associated with renal function and regulation of sodium homeostasis. We aimed to examine the associations of serum uromodulin levels and its genetic variants with longitudinal blood pressure (BP) changes and hypertension incidence/risk.Methods: A total of 514 participants from the original Baoji Salt-Sensitive Study cohort were genotyped to examine the associations of genetic variations in uromodulin gene with the longitudinal BP changes and the incidence of hypertension over 8 years of follow-up. In addition, 2,210 subjects from the cohort of Hanzhong Adolescent Hypertension Study were used to investigate the relationships between serum uromodulin levels and the risk of hypertension.Results: SNPs rs12917707 and rs12708631 in the uromodulin gene were significantly associated with the longitudinal BP changes over 8 years of follow-up. SNP rs12708631 was significantly associated with the incidence of hypertension over 8 years. In addition, gene-based analyses supported the associations of uromodulin gene with the longitudinal BP changes and hypertension incidence in Baoji Salt-Sensitive Study cohort. Furthermore, serum uromodulin levels in the hypertensive subjects were lower than in the normotensive subjects (25.5 ± 1.1 vs. 34.7 ± 0.7 ng/mL). Serum uromodulin levels decreased gradually as BP levels increased (34.6, 33.2, 27.8, and 25.0 ng/mL for subjects with normotension, high-normal, grade 1 hypertension, and grade 2 hypertension, respectively). Serum uromodulin was significantly associated with the lower risk of hypertension [0.978 (0.972–0.984)] in Hanzhong Adolescent Hypertension Study cohort.Conclusion: This study shows that uromodulin is associated with blood pressure progression and development of hypertension.

Calcium Signaling Silencing in Atrial Fibrillation: Implications for Atrial Sodium Homeostasis

Atrial fibrillation (AF) is the most common type of cardiac arrhythmia, affecting more than 33 million people worldwide. Despite important advances in therapy, AF’s incidence remains high, and treatment often results in recurrence of the arrhythmia. A better understanding of the cellular and molecular changes that (1) trigger AF and (2) occur after the onset of AF will help to identify novel therapeutic targets. Over the past 20 years, a large body of research has shown that intracellular Ca2+ handling is dramatically altered in AF. While some of these changes are arrhythmogenic, other changes counteract cellular arrhythmogenic mechanisms (Calcium Signaling Silencing). The intracellular Na+ concentration ([Na+])i is a key regulator of intracellular Ca2+ handling in cardiac myocytes. Despite its importance in the regulation of intracellular Ca2+ handling, little is known about [Na+]i, its regulation, and how it might be changed in AF. Previous work suggests that there might be increases in the late component of the atrial Na+ current (INa,L) in AF, suggesting that [Na+]i levels might be high in AF. Indeed, a pharmacological blockade of INa,L has been suggested as a treatment for AF. Here, we review calcium signaling silencing and changes in intracellular Na+ homeostasis during AF. We summarize the proposed arrhythmogenic mechanisms associated with increases in INa,L during AF and discuss the evidence from clinical trials that have tested the pharmacological INa,L blocker ranolazine in the treatment of AF.

Total Body Sodium Balance in Chronic Kidney Disease

Excess sodium intake is a leading but modifiable risk factor for mortality, with implications on hypertension, inflammation, cardiovascular disease, and chronic kidney disease (CKD). This review will focus mainly on the limitations of current measurement methods of sodium balance particularly in patients with CKD who have complex sodium physiology. The suboptimal accuracy of sodium intake and excretion measurement is seemingly more marked with the evolving understanding of tissue (skin and muscle) sodium. Tissue sodium represents an extrarenal influence on sodium homeostasis with demonstrated clinical associations of hypertension and inflammation. Measurement of tissue sodium has been largely unexplored in patients with CKD. Development and adoption of more comprehensive and dynamic assessment of body sodium balance is needed to better understand sodium physiology in the human body and explore therapeutic strategies to improve the clinical outcomes in the CKD population.

Endogenous Mammalian Cardiotonic Steroids—A New Cardiovascular Risk Factor?—A Mini-Review

The role of endogenous mammalian cardiotonic steroids (CTS) in the physiology and pathophysiology of the cardiovascular system and the kidneys has interested researchers for more than 20 years. Cardiotonic steroids extracted from toads or plants, such as digitalis, have been used to treat heart disease since ancient times. CTS, also called endogenous digitalis-like factors, take part in the regulation of blood pressure and sodium homeostasis through their effects on the transport enzyme called sodium–potassium adenosine triphosphatase (Na/K-ATPase) in renal and cardiovascular tissue. In recent years, there has been increasing evidence showing deleterious effects of CTS on the structure and function of the heart, vasculature and kidneys. Understanding the role of CTS may be useful in the development of potential new therapeutic strategies.

Sodium Homeostasis and Its Correlation with Mortality in Critically Ill Patients – A Retrospective Study in Northeast India

BACKGROUND Sodium is the most common electrolyte that gets imbalanced in hospitalised patients. Serum sodium abnormalities carry unacceptably high mortality. Our main objective was to study sodium homeostasis in critically ill patients and to correlate sodium imbalances with mortality in critically ill patients. METHODS This was a hospital based retrospective study conducted in Medicine Intensive Care Unit in Assam Medical College and Hospital in Dibrugarh, Assam, India, over a period of one year i.e., from February 2019 to January 2020. Hyponatremia has been defined as sodium level < 135mmol / L and hypernatremia as > 145mmol/L. All patients admitted in MICU of 12 years of age or more have been included in this study. Investigations such as serum creatinine, BUN, sodium, serum osmolality, urine sodium, and urine osmolality as well as neuroimaging were done. A total of 410 patients were studied. RESULTS Out of 410 patients, 106 (25.8 %) had hypernatremia, 84 (20.48 %) had hyponatremia and 220 (53.65 %) had normal sodium levels. 225 (54.87 %) patients died. There was a statistically significant correlation between sodium imbalance and death (p < 0.05). Mortality in hypernatremia (88.68%) was slightly higher than hyponatremia (79.34 %). It was observed that mortality in hypernatremia (OR = 20.7989, 95% CI: 10.6170 – 40.7454, p < 0.0001) and hyponatremia (OR = 10.2015, 95% CI: 5.6651 – 18.3704, p < 0.0001) were higher than that of normonatremia. Percentage of death was more in hypernatremia (88.68%) than hyponatremia (79.34%), but the difference was not statistically significant. (OR = 2.0388, 95% CI = 0.9302 to 4.4687, p = 0.0752). CONCLUSIONS Hyponatremia and hypernatremia are independent mortality factors in critically ill patients. Hypernatremia was more prevalent than hyponatremia in our study and accounted for more number of deaths. Timely and effective correction of sodium levels is important to save a patient’s life. Hypernatremia is often iatrogenic. Therefore proper monitoring of sodium is a must. KEYWORDS Sodium, Homeostasis, Mortality, Hyponatremia, Hypernatremia

Electrolytes in the ICU

Electrolyte disorders is an imbalance of certain ionized salts (sodium, potassium, calcium, bicarbonate, chloride) in the blood. Healthcare providers should be familiar with the principles of electrolyte physiology and pathophysiology. Disturbances in sodium homeostasis are primarily caused by volume abnormalities leading to primarily neurologic symptoms. Dyskalemias frequently present with cardiac manifestations therefore should be treated promptly before evaluating its cause. Ion deficiencies such as hypocalcemia, hypomagnesemia and hypophosphatemia should be corrected as they are associated with increased adverse events in critically ill patients.

Pathophysiology of Hypertension

Dr Irvine Page proposed the Mosaic Theory of Hypertension in the 1940s advocating that hypertension is the result of many factors that interact to raise blood pressure and cause end-organ damage. Over the years, Dr Page modified his paradigm, and new concepts regarding oxidative stress, inflammation, genetics, sodium homeostasis, and the microbiome have arisen that allow further refinements of the Mosaic Theory. A constant feature of this approach to understanding hypertension is that the various nodes are interdependent and that these almost certainly vary between experimental models and between individuals with hypertension. This review discusses these new concepts and provides an introduction to other reviews in this compendium of Circulation Research .

Onco-hypertension: Overview of hypertension with anti-cancer agents

Onco-hypertension is an emerging field investigating the relationship between hypertension and cancer. This paper details one part of this relationship—the effect of anti-cancer agents on blood pressure. We review the evidence linking targeted therapies, immunotherapy, traditional chemotherapies, and hormonal agents with hypertension. Proposed pathophysiological mechanisms vary by drug but include endothelial dysfunction, altered sodium homeostasis, and nephrotoxicity. Despite growing interest in the field, there is a paucity of data on the clinical significance of treatment related hypertension and the optimal management strategy. This should be a focus of future studies.

Nondipping Blood Pressure: Predictive or Reactive Failure of Renal Sodium Handling?

Blood pressure follows a daily rhythm, dipping during nocturnal sleep in humans. Attenuation of this dip (nondipping) is associated with increased risk of cardiovascular disease. Renal control of sodium homeostasis is essential for long-term blood pressure control. Sodium reabsorption and excretion have rhythms that rely on predictive/circadian as well as reactive adaptations. We explore how these rhythms might contribute to blood pressure rhythm in health and disease.