Sodium Homeostasis Research Articles

EARLY BLOOD PRESSURE AND MEDICATION CHANGES AFTER DELIVERY IN PATIENTS WITH POSTPARTUM HYPERTENSION

Objective: Postpartum Hypertension (PPHT) is defined as elevated blood pressure (BP) (systolic >= 140 mmHg, diastolic >= 90 mmHg) after delivery. PPHT is frequent and has various etiologies. In addition, several factors including hemodynamic fluctuations, sodium homeostasis, and stress attribute to dynamic changes in blood pressure. In this analysis, we focused on early BP trends and therapeutic intensity scores (TIS) trajectories during the first three months after delivery. Design and method: Starting in June 2020, patients were enrolled in the Basel-PPHT Cohort. Those with chronic hypertension (CH), hypertensive disorders of pregnancy (HDP), and de novo PPHT were eligible. This analysis included all patients with both a mobile App, which leads patients through guideline conform home BP measurements (HBPM), and a 24-hour ambulatory BP measurement 3 months after delivery. Therapy adjustments were done at the discretion of the treating physician via telemedicine consultations based on HBPM. BP and TIS trajectories were evaluated. TIS as quantification of treatment was defined as seen in Figure 1. Normotensive values were defined as systolic/diastolic <135mmHg/<85mmHg (HBPM and mean awake ABPM). BP comparisons between baseline visit (BV) defined as BP at enrollment to first post-baseline visit (FPBV) and landmark visit at 3 months post-delivery (LV). Results: 41 participants were included in this analysis. The mean (SD) age was 33(±4.9). BV, FPBV, and LV were conducted at a median (IQR)) of 3(3), 18(7), and 112 (28) days after delivery, respectively. Figure 1 shows BP and TIS trajectories. Mean systolic/diastolic BP decreased by 13(0.6)/2(1.7) mmHg between BV and FPBV, p=0.00/p=0.09, without a significant change of TIS. Whereas, changes in BP were not significant between FPBV and LV, but TIS significantly decreased (p<0.00). At LV median awake systolic/diastolic BP was 127(14)/ 82(9) mmHg, with 17% of participants on antihypertensive treatment, compared to 95% at BV. Conclusions: This analysis shows a significant decrease in BP during the transition period to ambulatory care. BP medication could be down-titrated in a relevant proportion of patients. These trends indicate the need for close monitoring of these patients in the early postpartum period.

High Salt Diet Regulates Intrarenal Sex Steroid Biosynthesis Pathway in a Sex-Specific Manner

Hypertension is more prevalent in men than age-matched pre-menopausal women. Sodium (Na+) homeostasis plays a major role in the control of blood pressure. Renal medullary estrogenic signaling promotes Na+ excretion in female, but not male Sprague Dawley (SD) rats implicating estrogen as a potential female-specific natriuretic factor. Recently we showed that the components of estrogen biosynthesis pathway are expressed in rat kidney suggesting the kidneys can produce estrogen locally to invoke this natriuretic response. It is unknown how dietary Na+ impacts biosynthesis of sex hormones. We hypothesize that a high salt (HS) diet enhances intrarenal estrogen biosynthesis pathway, and this enhancement is more pronounced in females compared to males. To test this hypothesis, we harvested the renal cortex from 14 week old male and female SD rats maintained on either a normal salt (NS 0.3% NaCl) or HS (4% NaCl) diet for 5 days. Given that cholesterol is the main precursor of steroid hormones, we measured the mRNA expression of HMG-CoA reductase (HMGCR), the key enzyme for cholesterol synthesis; and the steroidogenic acute regulatory protein (StAR), which transports cholesterol into the mitochondria for steroid commitment. We also assessed the mRNA expression of steroid 5α reductase (SRD5A), which converts testosterone to the non-aromatizable androgen, dihydrotestosterone. Further, we assessed aromatase, the key enzyme in estrogen biosynthesis, via immunohistochemistry. We found that renal HMGCR was more abundant in female compared to male rats maintained on a NS diet (P=0.0467). Increasing dietary salt intake upregulated renal HMGCR expression in male (P=0.0020), but not female rats (NS male; 100.0 ± 26.8 vs. NS female; 235.3 ± 23.2 vs. HS male 294.6 ± 42.0 vs HS female 314.6 ± 21.0 relative expression % NS male n=6-7/group). On a NS diet, renal StAR was more abundant in female compared to male rats (NS male; 100.0 ± 25.3 vs. NS female; 217.2 ± 36.5 relative expression % NS male P=0.0255 n=5-7/group). Increasing dietary salt did not alter expression of StAR in either sex. Similarly, renal SRD5A expression was higher in female compared to male (P=0.0141) rats. In addition, a HS diet increased the expression of SRD5A in female rats (0.0093) and tended to increase SRD5A expression in male (P=0.0849) rats (NS male; 100.0 ± 11.6 vs. NS female; 297.8 ± 37.7 vs. HS male 243.0 ± 39.2 vs HS female 498.8 ± 44.8 relative expression % NS male n=6-7/group). We also revealed that aromatase was expressed at a comparable level in male and female renal cortex, regardless of the diet (NS male; 2.4 ± 0.3 vs. NS female; 2.6 ± 0.3 vs. HS male 2.8 ± 0.3 vs HS female 1.9 ± 0.1 Average intensity x area mM2 n=6-9/group). Together, this data suggests that (i) the female kidney may be more primed for steroid biosynthesis and (ii) there is a sex-specific upregulation of the intrarenal sex steroid biosynthesis pathway in response to increasing dietary salt intake. Additional work is required to investigate the potential role of the kidney in androgen and estrogen production. A better understanding of this steroidogenic pathway could reveal novel sex-specific therapeutics for hypertension. T32DK007569-34 Carl Gottschalk Grant. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Recent advances in nano-enabled plant salt tolerance: Methods of application, risk assessment, opportunities and future perspectives

Salinity is a big issue threatening global food security. Among the different strategies, nanotechnology has shown tremendous potential for crop production under abiotic stresses, such as salinity. In this review, we discussed the environmental challenges associated with the different methods of nanomaterials application, including seed nanopriming, foliar, and soil/root application. Based on the previous research, nanopriming uses less nanomaterials and has minimum concerns about environmental safety and the food chain. We discussed in detail the preventive measures based on the application methods for the safe and sustainable use of nanomaterials in agriculture. Furthermore, we summarized the role of antioxidant enzyme-triggering nanomaterials and direct reactive oxygen species (ROS) scavenging nanomaterials (nanozymes) in plant salt tolerance. Nanomaterials improve sodium (Na+) and potassium (K+) homeostasis through various anatomical, physiological, and molecular mechanisms while improving plant salt tolerance. The role of nanomaterials in modulating plant photosynthesis and hormonal balance is largely overlooked. We also identified research gaps, providing guidelines for future research work. This review aimed to provide guidelines for the researchers to understand better the proper designing of NPs and different plant-related factors while using NPs for plant stress tolerance. It will help to improve the delivery efficiency of NPs into plants. Furthermore, after gaining sufficient scientific knowledge and better understanding, NPs can be integral to sustainable agriculture, saving costs and reducing biosafety concerns and environmental pollution.

Cardiorenal Syndromes and Their Role in Water and Sodium Homeostasis

Sodium is the main osmotically active ion in the extracellular fluid and its concentration goes hand in hand with fluid volume. Under physiological conditions, homeostasis of sodium and thus amount of fluid is regulated by neural and humoral interconnection of body tissues and organs. Both heart and kidneys are crucial in maintaining volume status. Proper kidney function is necessary to excrete regulated amount of water and solutes and adequate heart function is inevitable to sustain renal perfusion pressure, oxygen supply etc. As these organs are bidirectionally interconnected, injury of one leads to dysfunction of another. This condition is known as cardiorenal syndrome. It is divided into five subtypes regarding timeframe and pathophysiology of the onset. Hemodynamic effects include congestion, decreased cardiac output, but also production of natriuretic peptides. Renal congestion and hypoperfusion leads to kidney injury and maladaptive activation of renin-angiotensin-aldosterone system and sympathetic nervous system. In cardiorenal syndromes sodium and water excretion is impaired leading to volume overload and far-reaching negative consequences, including higher morbidity and mortality of these patients. Keywords: Cardiorenal syndrome • Renocardiac syndrome • Volume overload • Sodium retention

Altered Plasma Membrane Lipid Composition in Hypertensive Neutrophils Impacts Epithelial Sodium Channel (ENaC) Endocytosis.

Biological membranes are composed of a lipid bilayer with embedded proteins, including ion channels like the epithelial sodium channel (ENaC), which are critical for sodium homeostasis and implicated in arterial hypertension (HTN). Changes in the lipid composition of the plasma membrane can significantly impact cellular processes related to physiological functions. We hypothesized that the observed overexpression of ENaC in neutrophils from HTN patients might result from alterations in the structuring domains within the plasma membrane, disrupting the endocytic processes responsible for ENaC retrieval. This study assessed the structural lipid composition of neutrophil plasma membranes from HTN patients along with the expression patterns of key elements regulating ENaC at the plasma membrane. Our findings suggest alterations in microdomain structure and SGK1 kinase activity, which could prolong ENaC presence on the plasma membrane. Additionally, we propose that the proteasomal and lysosomal degradation pathways are insufficient to diminish ENaC presence at the plasma membrane in HTN. These results highlight the importance of understanding ENaC retrieval mechanisms and suggest that targeting these mechanisms could provide insights for developing drugs to prevent and treat HTN.

Populus euphratica PeNADP-ME interacts with PePLDδ to mediate sodium and ROS homeostasis under salinity stress

Populus euphratica phospholipase Dδ (PePLDδ) is transcriptionally regulated and mediates reactive oxygen species (ROS) and ion homeostasis under saline conditions. The purpose of this study is to explore the post-transcriptional regulation of PePLDδ in response to salt environment. P. euphratica PePLDδ was shown to interact with the NADP-dependent malic enzyme (NADP-ME) by screening the yeast two-hybrid libraries. The transcription level of PeNADP-ME increased upon salt exposure to NaCl (200 mM) in leaves and roots of P. euphratica. PeNADP-ME had a similar subcellular location with PePLDδ in the cytoplasm, and the interaction between PeNADP-ME and PePLDδ was further verified by GST pull-down and yeast two-hybrid. To clarify whether PeNADP-ME interacts with PePLDδ to enhance salt tolerance, PePLDδ and PeNADP-ME were overexpressed singly or doubly in Arabidopsis thaliana. Dual overexpression of PeNADP-ME and PePLDδ resulted in an even more pronounced improvement in salt tolerance compared with single transformants overexpressing PeNADP-ME or PePLDδ alone. Greater Na+ limitation and Na+ efflux in roots were observed in doubly overexpressed plants compared with singly overexpressed plants with PeNADP-ME or PePLDδ. Furthermore, NaCl stimulation of SOD, APX, and POD activity and transcription were more remarkable in the doubly overexpressed plants. It is noteworthy that the enzymic activity of NADP-ME and PLD, and total phosphatidic acid (PA) concentrations were significantly higher in the double-overexpressed plants than in the single transformants. We conclude that PeNADP-ME interacts with PePLDδ in Arabidopsis to promote PLD-derived PA signaling, conferring Na+ extrusion and ROS scavenging under salt stress.

Postprandial sodium sensing by enteric neurons in Drosophila.

Sodium is essential for all living organisms1. Animals including insects and mammals detect sodium primarily through peripheral taste cells2-7. It is not known, however, whether animals can detect this essential micronutrient independently of the taste system. Here, we report that Drosophila Ir76b mutants that were unable to detect sodium2 became capable of responding to sodium following a period of salt deprivation. From a screen for cells required for the deprivation-induced sodium preference, we identified a population of anterior enteric neurons, which we named internal sodium-sensing (INSO) neurons, that are essential for directing a behavioural preference for sodium. Enteric INSO neurons innervate the gut epithelia mainly through their dendritic processes and send their axonal projections along the oesophagus to the brain and to the crop duct. Through calcium imaging and CaLexA experiments, we found that INSO neurons respond immediately and specifically to sodium ions. Notably, the sodium-evoked responses were observed only after a period of sodium deprivation. Taken together, we have identified a taste-independent sodium sensor that is essential for the maintenance of sodium homeostasis.

Role of Copeptin in Predicting Postoperative Hyponatremia and Hypernatremia in Patients Undergoing Endoscopic Pituitary Adenoma Surgery.

Arginine vasopressin (AVP) is an important hormone responsible for maintaining sodium homeostasis after pituitary surgery. The measurement of AVP levels is difficult because of its short half-life (t 1/2 ). Copeptin is a preprohormone of AVP, and it is a more stable peptide, which can be used as surrogate marker for AVP. This study aims to assess the role of copeptin as a predictor of postoperative hyponatremia and hypernatremia in patients undergoing endoscopic pituitary adenoma surgery. This prospective study included 50 patients who underwent endoscopic pituitary adenoma surgery. Serum copeptin levels of these patients were assessed (1) preoperatively (C1), (2) at extubation (C2), and (3) postoperative day 4 (C3). Perioperative data regarding fluid and sodium balance were collected from patients. Statistical analysis was done using the above data. The copeptin values were assessed against the sodium disturbances. 100% of patients who developed transient diabetes insipidus had a relative decrease in C2 from C1 ( P - .0002). 88% of patients who developed early hyponatremia had a relative increase in C2 as compared with C1 ( P < .01). 75% of patients who developed delayed hyponatremia had a relative increase in C3 as compared with C1 ( P = .003). A relative increase or decrease in early change in copeptin (C2-C1) can predict development of early hyponatremia or transient central diabetes insipidus, respectively. A relative increase in delayed change in copeptin (C3-C1) can predict development of delayed hyponatremia.

Elevated CO2-conferred sodium homeostasis is linked to abscisic acid-mediated stomatal closure and signalling pathway in tomato plants

Soil salinity hampers plant performance. Elevated atmospheric CO2 (e[CO2]) could alleviate the detrimental effect of salinity on plants but whether abscisic acid (ABA) is involved in this process is unclear. To address this issue, three tomato (Solanum lycopersicum) genotypes with varying endogenous ABA concentrations (wild-type AC, ABA-deficient mutant flacca and ABA-overproduction line SP5) were grown in pots under ambient (400 μmol · mol–1) or elevated (800 μmol · mol–1) CO2 with or without the addition of 100 mmol · L−1sodium chloride (NaCl). The results showed that e[CO2] favored ion homeostasis by decreasing root-to-shoot delivery of Na+, which was mainly attributed to lowered transpiration rate rather than altered xylem-sap Na+ concentration. In AC and SP5, the low transpiration rate of e[CO2]-plants under salinity was accompanied by enhanced endogenous ABA levels, which might play a role in upregulating the abundance of specific transcripts related to Na+ homeostasis (i.e., SALT OVERLY SENSITIVE) under salt stress. In flacca, e[CO2]-induced Na+ homeostasis was abolished, which could be ascribed to the low and unaltered ABA levels, albeit the ethylene biosynthesis was enhanced in flacca under salt stress, indicating an antagonistic relationship between ABA and ethylene. Furthermore, e[CO2] inhibited ethylene biosynthesis under salt stress in all three genotypes. The results enrich our comprehension of the fundamental processes of e[CO2]-conferred salt tolerance in tomato.

Corin deficiency alleviates mucosal lesions in a mouse model of colitis induced by dextran sulfate sodium

AimsHigh dietary salt consumption is a risk factor for inflammatory bowel disease (IBD). Corin is a protease that activates atrial natriuretic peptide (ANP), thereby regulating sodium homeostasis. Corin acts in multiple tissues, including the intestine. In mice, corin deficiency impairs intestinal sodium excretion. This study aims to examine if reduced intestinal sodium excretion alters the pathophysiology of IBD. Main methodsWild-type (WT), Corin knockout (KO), and Corin kidney conditional KO (kcKO) mice were tested in a colitis model induced by dextran sulfide sodium (DSS). Effects of ANP on DSS-induced colitis were tested in WT and Corin KO mice. Body weight changes in the mice were monitored. Necropsy, histological analysis, and immunostaining studies were conducted to examine colon length and mucosal lesions. Fecal sodium levels were measured. RT-PCR was done to analyze proinflammatory genes in colon samples. Key findingsDSS-treated Corin KO mice had an ameliorated colitis phenotype with less body weight loss, longer colon lengths, smaller mucosal lesions, lower disease scores, more preserved goblet cells, and suppressed proinflammatory genes in the colon. In longitudinal studies, the DSS-treated Corin KO mice had delayed onset of colon mucosal lesions. ANP administration lessened the colitis in WT, but not Corin KO, mice. Analyses of WT, Corin KO, and Corin kcKO mice indicated that fecal sodium excretion, controlled by intestinal corin, may regulate inflammatory responses in DSS-induced colitis in mice. SignificanceOur findings indicate a role of corin in intestinal pathophysiology, suggesting that reduced intestinal sodium level may offer protective benefits against IBD.

SGLT2 Inhibition in Heart Failure: Clues to Cardiac Effects?

Following the publication of several landmark clinical trials such as dapagliflozin in patients with heart failure and reduced ejection fraction, dapagliflozin evaluation to improve the lives of patients with preserved ejection fraction heart failure, and empagliflozin outcome trial in patients with chronic heart failure with preserved ejection fraction, sodium-glucose cotransport 2 inhibitors have been rapidly incorporated as a guideline-directed therapy in the treatment of heart failure. Moreover, their benefits appear to extend across the spectrum of left ventricular dysfunction which in some respects, can be seen as the holy grail of heart failure pharmacotherapy. Despite its plethora of proven cardioprotective benefits, the mechanisms by which it exerts these effects remain poorly understood, however, it is clear that these extend beyond that of promotion of glycosuria and natriuresis. Several hypotheses have emerged over the years including modification of cardiovascular risk profile via weight reduction, improved glucose homeostasis, blood pressure control, and natriuretic effect; however, these mechanisms do not fully explain the potent effects of the drug demonstrated in large-scale randomized trials. Other mechanisms may be at play, specifically the down-regulation of inflammatory pathways, improved myocardial sodium homeostasis, modulation of profibrotic pathways, and activation of nutrient deprivation signaling pathways promoting autophagic flux. This review seeks to summarize the cardioprotective benefits demonstrated in major clinical trials and provide a succinct review of the current theories of mechanisms of action, based on the most recent evidence derived from both clinical and laboratory data.

Excessive sodium supplementation but not fluid load is correlated with overall morbidity in extremely low birth weight infants.

Sodium homeostasis in extremely low birth weight (ELBW)infants is critical. While a lack of sodium delays growth, excessive supplementation increases morbidity. We performed a single-center retrospective study on sodium and fluid management during the first 2 weeks of live including all ELBW infants born between June 1, 2017 and May 31, 2019. Forty-seven patients (median GA 26 + 6 weeks, median BW 845 g) were included. Mean sodium intake was above the ESPGHAN recommendation, 4.58 mmol/kg/day during the first 2 days and 1.99 mmol/kg/day during the following period. Incidence of PDA, IVH, and ROP was directly associated with sodium intake (OR1.6, 1.3, and 1.4, respectively), but not with fluid supplementation. No association to BPD was found. The most important source for inadvertent sodium intake were 0.9% saline given by arterial lines. Sodium supplementation did not correlate directly with serum sodium levels, but a linear regression model combining sodium intake and fluid supplementation was able to predict serum sodium changes 24-48 h in advance (correlation coefficient of 0.294, p < 0.05). Sodium application substantially exceeded ESPGHAN recommendations in ELBW infants. An excess in sodium was associated with an overall increased morbidity, justifying increased efforts to identify inadvertent sodium sources in these patients with the aim to decrease sodium excess.

Role of Acetic Acid and Nitric Oxide against Salinity and Lithium Stress in Canola (Brassica napus L.).

In this study, canola (Brassica napus L.) seedlings were treated with individual and combined salinity and lithium (Li) stress, with and without acetic acid (AA) or nitric acid (NO), to investigate their possible roles against these stresses. Salinity intensified Li-induced damage, and the principal component analysis revealed that this was primarily driven by increased oxidative stress, deregulation of sodium and potassium accumulation, and an imbalance in tissue water content. However, pretreatment with AA and NO prompted growth, re-established sodium and potassium homeostasis, and enhanced the defense system against oxidative and nitrosative damage by triggering the antioxidant capacity. Combined stress negatively impacted phenylalanine ammonia lyase activity, affecting flavonoids, carotenoids, and anthocyanin levels, which were then restored in canola plants primed with AA and NO. Additionally, AA and NO helped to maintain osmotic balance by increasing trehalose and proline levels and upregulating signaling molecules such as hydrogen sulfide, γ-aminobutyric acid, and salicylic acid. Both AA and NO improved Li detoxification by increasing phytochelatins and metallothioneins, and reducing glutathione contents. Comparatively, AA exerted more effective protection against the detrimental effects of combined stress than NO. Our findings offer novel perspectives on the impacts of combining salt and Li stress.

Urinary Klotho Excretion: A Key Regulator of Sodium Homeostasis in Chronic Kidney Disease Stage 2-4.

BACKGROUND Soluble alpha-klotho (klotho) is considered an important regulator of mineral homeostasis in patients with chronic kidney disease (CKD). Since the mineral transport proteins are located on the apical membrane of renal tubular cells, we hypothesized that urine klotho may also be involved in their homeostasis. We aimed to investigate the associations between serum and urine klotho and their impacts on mineral homeostasis in patients with stage 2 to 4 CKD. MATERIAL AND METHODS Serum, spot urine, and 24-h urine of klotho were measured by using enzyme-linked immunosorbent assay. Fractional excretion of sodium, potassium, calcium, phosphate, magnesium, and klotho were calculated. RESULTS A total of 53 patients with CKD stages 2 to 4 were enrolled in this cross-sectional study. The mean age was 71.1±10.5 years, and 68% were men. Linear regression analysis showed that serum log-transformed klotho was negatively associated with log-transformed fractional excretion of klotho (log-FEKlotho) (ß=-0.085, P=0.02), showing that urinary klotho excretion could negatively regulate serum klotho levels. Moreover, our multivariate stepwise regression showed log-fractional excretion of sodium was positively associated with log-FEKlotho (ß=0.138, P=0.032). This implied urinary klotho excretion positively regulated urinary sodium excretion. CONCLUSIONS Our study showed that urine klotho excretion resulted in decreased serum klotho levels and enhanced urinary sodium excretion in patients with CKD stages 2 to 4. In addition to serum klotho, we found, for the first time, that urine klotho also played a significant role in sodium homeostasis.

Identification of the High-Affinity Potassium Transporter Gene Family (HKT) in Brassica U-Triangle Species and Its Potential Roles in Abiotic Stress in Brassica napus L.

Members of the high-affinity potassium transporter (HKT) protein family regulate the uptake and homeostasis of sodium and potassium ions, but little research describes their roles in response to abiotic stresses in rapeseed (Brassica napus L.). In this study, we identified and characterized a total of 36 HKT genes from the species comprising the triangle of U model (U-triangle species): B. rapa, B. nigra, B. oleracea, B. juncea, B. napus, and B. carinata. We analyzed the phylogenetic relationships, gene structures, motif compositions, and chromosomal distributions of the HKT family members of rapeseed. Based on their phylogenetic relationships and assemblage of functional domains, we classified the HKT members into four subgroups, HKT1;1 to HKT1;4. Analysis of the nonsynonymous substitutions (Ka), synonymous substitutions (Ks), and the Ka/Ks ratios of HKT gene pairs suggested that these genes have experienced strong purifying selective pressure after duplication, with their evolutionary relationships supporting the U-triangle theory. Furthermore, the expression profiles of BnaHKT genes varies among potassium, phytohormone and heavy-metal treatment. Their repression provides resistance to heavy-metal stress, possibly by limiting uptake. Our results systematically reveal the characteristics of HKT family proteins and their encoding genes in six Brassica species and lay a foundation for further exploration of the role of HKT family genes in heavy-metal tolerance.

Sodium homeostasis and signalling: The core and the hub of astrocyte function

Neuronal activity and neurochemical stimulation trigger spatio-temporal changes in the cytoplasmic concentration of Na+ ions in astrocytes. These changes constitute the substrate for Na+ signalling and are fundamental for astrocytic excitability. Astrocytic Na+ signals are generated by Na+ influx through neurotransmitter transporters, with primary contribution of glutamate transporters, and through cationic channels; whereas recovery from Na+ transients is mediated mainly by the plasmalemmal Na+/K+ ATPase. Astrocytic Na+ signals regulate the activity of plasmalemmal transporters critical for homeostatic function of astrocytes, thus providing real-time coordination between neuronal activity and astrocytic support.

ERRα Acts as a Bridge of Mitochondria and Sodium Homeostasis in Proximal Tubular Epithelial Cells Under Diabetes

ERRα Acts as a Bridge of Mitochondria and Sodium Homeostasis in Proximal Tubular Epithelial Cells Under Diabetes

Early-life sodium deprivation programs long-term changes in ingestive behaviors and energy expenditure in C57BL/6J mice.

Postnatal growth failure remains a significant problem for infants born prematurely, despite aggressive efforts to improve perinatal nutrition. Though often dysregulated in early life when children are born preterm, sodium (Na) homeostasis is vital to achieve optimal growth. We hypothesize that insufficient Na supply in this critical period contributes to growth restriction and programmed risks for cardiometabolic disease in later adulthood. Thus, we sought to ascertain the effects of prolonged versus early-life Na depletion on weight gain, body composition, food and water intake behaviors, and energy expenditure in C57BL/6J mice. In one study, mice were provided a low (0.04%)- or normal/high (0.30%)-Na diet between 3 and 18 wk of age. Na-restricted mice demonstrated delayed growth and elevated basal metabolic rate. In a second study, mice were provided 0.04% or 0.30% Na diet between 3 and 6 wk of age and then returned to standard (0.15%)-Na diet through the end of the study. Na-restricted mice exhibited growth delays that quickly caught up on return to standard diet. Between 6 and 18 wk of age, previously restricted mice exhibited sustained, programmed changes in feeding behaviors, reductions in total food intake, and increases in water intake and aerobic energy expenditure while maintaining normal body composition. Although having no effect in control mice, administration of the ganglionic blocker hexamethonium abolished the programmed increase in basal metabolic rate in previously restricted mice. Together these data indicate that early-life Na restriction can cause programmed changes in ingestive behaviors, autonomic function, and energy expenditure that persist well into adulthood.

MTORC1 and SGLT2 Inhibitors-A Therapeutic Perspective for Diabetic Cardiomyopathy.

Diabetic cardiomyopathy is a critical diabetes-mediated co-morbidity characterized by cardiac dysfunction and heart failure, without predisposing hypertensive or atherosclerotic conditions. Metabolic insulin resistance, promoting hyperglycemia and hyperlipidemia, is the primary cause of diabetes-related disorders, but ambiguous tissue-specific insulin sensitivity has shed light on the importance of identifying a unified target paradigm for both the glycemic and non-glycemic context of type 2 diabetes (T2D). Several studies have indicated hyperactivation of the mammalian target of rapamycin (mTOR), specifically complex 1 (mTORC1), as a critical mediator of T2D pathophysiology by promoting insulin resistance, hyperlipidemia, inflammation, vasoconstriction, and stress. Moreover, mTORC1 inhibitors like rapamycin and their analogs have shown significant benefits in diabetes and related cardiac dysfunction. Recently, FDA-approved anti-hyperglycemic sodium-glucose co-transporter 2 inhibitors (SGLT2is) have gained therapeutic popularity for T2D and diabetic cardiomyopathy, even acknowledging the absence of SGLT2 channels in the heart. Recent studies have proposed SGLT2-independent drug mechanisms to ascertain their cardioprotective benefits by regulating sodium homeostasis and mimicking energy deprivation. In this review, we systematically discuss the role of mTORC1 as a unified, eminent target to treat T2D-mediated cardiac dysfunction and scrutinize whether SGLT2is can target mTORC1 signaling to benefit patients with diabetic cardiomyopathy. Further studies are warranted to establish the underlying cardioprotective mechanisms of SGLT2is under diabetic conditions, with selective inhibition of cardiac mTORC1 but the concomitant activation of mTORC2 (mTOR complex 2) signaling.

FRI354 Therapeutic Potential Of Oxcarbazepine In Central Diabetes Insipidus

Abstract Disclosure: S. Pittampalli: None. V. Pattan: None. D. Das: None. U. Munasinghe: None. Introduction: Postoperative central Diabetes insipidus is usually transient but can be persistent. Persistent central Diabetes insipidus is prone to dose fluctuations in clinically unstable patients, especially when concomitant medications influence sodium and water homeostasis. Clinical Case: A 24-year-old female with headache and confusion had sellar and suprasellar mass of 6 cm x 4 cm with moderate to severe hydrocephalus and underwent Right craniotomy with debulking of the mass and pathology showed pilocytic astrocytoma. Postoperative course was complicated by short-term memory loss, right-sided weakness, adrenal insufficiency, and visual impairment. Repeat imaging showed increased size of suprasellar mass consequently requiring a transnasal transphenoidal resection. Post-operative neurological worsening was noted along with diffuse subarachnoid/ intraventricular hemorrhage with intraparenchymal hematoma in the right frontal lobe on CTA head. Hospital course included tracheostomy with mechanical ventilation. She had panhypopituitarism including CDI. CDI was initially managed by DDAVP 10mcg intranasal nightly and free water flushes. She had central adrenal insufficiency and central hypothyroidism treated by hydrocortisone and levothyroxine respectively. Hospital stay lasted for several months with multiple adjustments to the DDAVP dosage and free water flushes due to fluctuating serum sodium levels. She was started on levetiracetam 750 mg twice daily and oxcarbazepine 300 mg twice daily for seizure like activity. After two months, the oxcarbazepine dose was increased to 450 mg twice daily and later to 600 mg twice daily for breakthrough seizures. DDAVP was then discontinued as she developed hyponatremia. The dose of oxcarbazepine was reduced to 450 mg twice daily and she was subsequently discharged to a facility off DDAVP. Discussion: Postoperative CDI managed by DDAVP was complicated with oxcarbazepine-induced hyponatremia. CDI and sodium levels were controlled with oxcarbazepine after DDAVP discontinuation. Thus, oxcarbazepine has therapeutic potential as an antidiuretic agent as it can stimulate collecting tubule V2 receptor - G protein complex independent of ADH. Presentation: Friday, June 16, 2023