Electrolyte Homeostasis Research Articles

Mineralocorticoid Receptor and Sleep Quality in Chronic Kidney Disease.

The classical function of the mineralocorticoid receptor (MR) is to maintain electrolytic homeostasis and control extracellular volume and blood pressure. The MR is expressed in the central nervous system (CNS) and is involved in the regulation of the hypothalamic-pituitary-adrenal (HPA) axis as well as sleep physiology, playing a role in the non-rapid eye movement (NREM) phase of sleep. Some patients with psychiatric disorders have very poor sleep quality, and a relationship between MR dysregulation and this disorder has been found in them. In addition, the MR is involved in the regulation of the renal peripheral clock. One of the most common comorbidities observed in patients with chronic kidney disease (CKD) is poor sleep quality. Patients with CKD experience sleep disturbances, including reduced sleep duration, sleep fragmentation, and insomnia. To date, no studies have specifically investigated the relationship between MR activation and CKD-associated sleep disturbances. However, in this review, we analyzed the environment that occurs in CKD and proposed two MR-related mechanisms that may be responsible for these sleep disturbances: the circadian clock disruption and the high levels of MR agonist observed in CKD.

RRAGD variants cause cardiac dysfunction in a zebrafish model.

The Ras-related GTP-binding protein D (RRAGD) gene plays a crucial role in cellular processes. Recently, RRAGD variants found in patients have been implicated in a novel disorder with kidney tubulopathy and dilated cardiomyopathy. Currently, the consequences of RRAGD variants at the organismal level are unknown. Therefore, this study investigated the impact of RRAGD variants on cardiac function using a zebrafish embryo model. Furthermore, the potential usage of rapamycin, an mTOR inhibitor, as a therapy was assessed in this model. Zebrafish embryos were injected with RRAGD p.S76L and p.P119R cRNA and the resulting heart phenotypes were studied. Our findings reveal that overexpression of RRAGD mutants resulted in decreased ventricular fractional shortening, ejection fraction, and pericardial swelling. In RRAGD S76L-injected embryos, lower survival and heartbeat were observed, whereas survival was unaffected in RRAGD P119R embryos. These observations were reversible following therapy with the mTOR inhibitor rapamycin. Moreover, no effects on electrolyte homeostasis were observed. Together, these findings indicate a crucial role of RRAGD in cardiac function. In the future, the molecular mechanisms by which RRAGD variants result in cardiac dysfunction and if the effects of rapamycin are specific for RRAGD-dependent cardiomyopathy should be studied in clinical studies.NEW & NOTEWORTHY The resultant heart-associated phenotypes in the zebrafish embryos of this study serve as a valuable experimental model for this rare cardiomyopathy. Moreover, the potential therapeutic property of rapamycin in cardiac dysfunctions was highlighted, making this study a pivotal step toward prospective clinical applications.

Polymyxin-B induced bartter-like syndrome: an unusual adverse effect

Introduction and Importance: Bartter syndrome is a rare autosomal recessive disorder affecting renal tubular function, leading to electrolyte and volume homeostasis disturbances. It can also manifest as Bartter-like syndrome, a rare side effect of certain medications. Polymyxin-B, used to treat multidrug-resistant infections, is infrequently associated with BLS, making early recognition crucial to prevent severe electrolyte imbalances. Case Presentation: A 73-year-old female with coronary artery disease, COPD, hyperlipidemia, and other comorbidities presented with fever, respiratory distress, and hypoxia on mechanical ventilation. Initial labs showed leukocytosis, anemia, and normal potassium. Despite broad-spectrum antibiotics, sputum cultures revealed pandrug-resistant Acinetobacter baumannii, sensitive only to Polymyxin-B. After six days of Polymyxin-B, the patient developed fever, hypotension, hypokalemia, hypomagnesemia, and polyuria. Urine studies indicated increased potassium excretion. A diagnosis of Bartter like syndrome was made. Polymyxin-B was discontinued, and the patient’s electrolytes normalized, resolving the polyuria. She was discharged with daily potassium and magnesium supplements. Clinical Discussion: Bartter-like syndrome can result from Polymyxin-B-induced tubular dysfunction, characterized by hypokalemia and hypomagnesemia. Close electrolyte monitoring is essential for patients receiving this antibiotic, particularly in those with complex medical conditions. Early recognition allowed for timely discontinuation of Polymyxin-B, which rapidly reversed the electrolyte disturbances. Conclusion: This case underscores the importance of recognizing Polymyxin-B-induced Bartter-like syndrome. Clinicians should be vigilant for electrolyte disturbances in patients undergoing treatment with Polymyxin-B, ensuring timely interventions to mitigate adverse outcomes.

Rho-associated, coiled-coil-containing protein kinase 2 regulates expression of mineralocorticoid receptor to mediate sodium reabsorption in mice

The mineralocorticoid receptor (MR) is a member of the nuclear receptor family that was initially identified to regulate blood pressure through its ability to modulate kidney sodium handling in response to aldosterone. MR can be regulated by signals other than aldosterone; however, the detailed mechanisms remain to be elucidated. We found that MR is controlled in a Rho-associated coiled-coil-containing protein kinase 2 (ROCK2)-dependent manner. Mice with a specific deletion of ROCK2 in the kidney tubules showed decreased MR expression levels and increased urinary excretion of sodium. Mechanistically, signal transducer and activator of transcription 3 (STAT3) is a key molecule that mediates MR expression in these mice. This study highlights an important role of tubular ROCK2 in electrolyte homeostasis.

A systematic review of lithium biology and pharmacology and toxicological evaluation of new organic lithium salts

Objective: to systematize scientific data on biomedical studies investigating trace element lithium over the past 70 years; evaluate toxic properties of lithium ascorbate (LiAsc) as an important promising candidate molecule.Material and methods. An analysis of 49,959 publications on lithium biomedical research retrieved from PubMed/MEDLINE database was carried out using modern data mining methods developed within the framework of topological approach to recognizing (Yu.I. Zhuravlev scientific school). Publications found by experts and not indexed in PubMed/MEDLINE were used in discussing the results of a systematic analysis of publications array retrieved from PubMed/MEDLINE. An experimental study of chronic 180 day-long LiAsc (at doses of 5, 50 and 150 mg/kg) toxicity was performed on 36 “Soviet chinchilla” rabbits by assessing local irritant action. Intoxication clinical picture, body weight dynamics, water and food intake as well as physiological, hematological and biochemical parameters were analyzed.Results. Classification and systematization of all currently available publications on lithium biology and medicine were performed. It was shown that pharmacological applications of lithium salts in mental disorders as well as lithium effects on simple sugars metabolism, lipid metabolism, blood pressure regulation, hematopoiesis, inflammation and tumor growth inhibition, neurotransmitter homeostasis, neurotrophic and neuroprotective molecular mechanisms as well as homeostasis of other electrolytes comprised promising fields of lithium drug research. The prospects for using organic lithium salts, particularly LiAsc, for various therapeutic goals were also discussed. 180-day-long oral administration of LiAsc at doses of 5, 50, 150 mg/kg resulted in no macroscopic signs of local inflammatory reaction while examining its local irritant effect.Conclusion. The lithium-ion effect on neurotransmitters promotes neuroprotection and reduces a risk of addiction. The antihypertensive, antiatherosclerotic, antidiabetic, antitumor and neurotrophic effects related to organic lithium salts may be beneficial in various therapeutic applications.

Plasma exchange and intravenous immunoglobulin prolonged the survival of a porcine kidney xenograft in a sensitized, deceased human recipient.

The primary limitation to kidney transplantation is organ shortage. Recent progress in gene editing and immunosuppressive regimens has made xenotransplantation with porcine organs a possibility. However, evidence in pig-to-human xenotransplantation remains scarce, and antibody-mediated rejection (AMR) is a major obstacle to clinical applications of xenotransplantation. We conducted a kidney xenotransplantation in a deceased human recipient using a porcine kidney with five gene edits (5GE) on March 25th, 2024 at Xijing Hospital, China. Clinical-grade immunosuppressive regimens were employed, and the observation period lasted 22days. We collected and analyzed the xenograft function, ultrasound findings, sequential protocol biopsies, and immune surveillance of the recipient during the observation. The combination of 5GE in the porcine kidney and clinical-grade immunosuppressive regimens prevented hyperacute rejection. The xenograft kidney underwent delayed graft function in the first week, but urine output increased later and the single xenograft kidney maintained electrolyte and pH homeostasis from postoperative day (POD) 12 to 19. We observed AMR at 24h post-transplantation, due to the presence of pre-existing anti-porcine antibodies and cytotoxicity before transplantation; this AMR persisted throughout the observation period. Plasma exchange and intravenous immunoglobulin treatment mitigated the AMR. We observed activation of latent porcine cytomegalovirus toward the end of the study, which might have contributed to coagulation disorder in the recipient. 5GE and clinical-grade immunosuppressive regimens were sufficient to prevent hyperacute rejection during pig-to-human kidney xenotransplantation. Pre-existing anti-porcine antibodies predisposed the xenograft to AMR. Plasma exchange and intravenous immunoglobulin were safe and effective in the treatment of AMR after kidney xenotransplantation.

The impact of mineralocorticoid and glucocorticoid receptor interaction on corticosteroid transcriptional outcomes

The mineralocorticoid and glucocorticoid receptors (MR and GR, respectively) are members of the steroid receptor subfamily of nuclear receptors. Their main function is to act as ligand-activated transcription factors, transducing the effects of corticosteroid hormones (aldosterone and glucocorticoids) by modulating gene expression. Corticosteroid signaling is essential for homeostasis and adaptation to different forms of stress. GR responds to glucocorticoids by regulating genes involved in development, metabolism, immunomodulation and brain function. MR is best known for mediating the effects of aldosterone, a key hormone controlling electrolyte and water homeostasis. In addition to aldosterone, MR binds glucocorticoids (cortisol and corticosterone) with equally high affinity. This ligand promiscuity has important repercussions to understand MR function, as well as glucocorticoid signaling. MR and GR share significant sequence and structural similarities, regulate overlapping sets of genes and are able to interact forming heteromeric complexes. However, the precise role of these heteromers in regulating corticosteroid-regulated transcriptional outcomes remains an open question. In this review, we examine the evidence supporting MR-GR heteromerization, the molecular determinants of complex formation and their possible role in differential regulation of transcription in different cellular contexts and ligand availability.

8359 Increased hepatic SGK1 activity promotes metabolic dysfunction-associated fatty liver disease in a sex-dependent manner

Abstract Disclosure: A. Vastola-Mascolo: None. G. Hernández: None. D. Alvarez de la Rosa: None. The serum and glucocorticoid-induced kinase 1 (SGK1) is a Ser/Thr kinase with key roles in fluid and electrolyte homeostasis, blood pressure regulation and energy metabolism. Its expression is controlled by steroid hormones such as glucocorticoids, mineralocorticoids and estrogen, in addition to other stimuli such as glucose. SGK1 activation mainly depends on the PI3 kinase pathway, implicating it in insulin signaling. Previous work from our laboratory demonstrated that a systemic increase in SGK1 activity exacerbates diet-induced development of metabolic syndrome in mouse, characterized by obesity, glucose intolerance, insulin resistance, dyslipidemia and hypertension. In addition, a high-fat diet rapidly led to the development of hepatic steatosis. We now test the hypothesis that at least part of the effects of increased systemic SGK1 activity promoting the development of metabolic syndrome are due to alterations in liver glucose or lipid handling. To that end we developed a mouse strain with hepatocyte-specific transgenic SKG1 expression and challenged it with high-fat or high-fat/high-sucrose diets. Our results show sex differences in the development of obesity, with a marked increase in body weight in female, but not male transgenic animals. Glucose homeostasis was normal in both sexes. Increased obesity in females correlated with increased lipid accumulation in the liver. However, liver fibrosis, inflammation and dyslipidemia were more marked in male animals, further suggesting an interaction between SGK1 and sex steroid hormone signaling. Our results demonstrate a key role of SGK1 in liver lipid metabolism and suggest a crosstalk between this signaling pathway and sex hormones, which determine a more negative outcome in male animals. Presentation: 6/1/2024

Characterization of a novel variant in KCNJ16, encoding Kir5.1 channel.

The essential role of the inwardly rectifying potassium channel Kir5.1 (KCNJ16) in controlling electrolyte homeostasis and blood pressure has been demonstrated in human and animal studies. Previous studies have identified several bi-allelic mutations of KCNJ16 in humans, causing severe hypokalemia, renal salt wasting, and disturbed acid-base homeostasis. Here, we identified a novel homozygous variant of KCNJ16, I26T, in an Amish patient affected with polydipsia, developmental delay, and chronic metabolic acidosis with low serum bicarbonate concentration. Subsequently, we generated the rat model with I26T mutation using Dahl salt-sensitive rat (I26T rat) to characterize this variant. The male mutant rats displayed similar blood pressure and electrolyte homeostasis under baseline and with a high salt (4% NaCl) challenge. Blood pH, HCO3 - and renal damage also remained similar between WT and I26T rats after high salt challenge. Additionally, single-channel patch clamp analysis revealed similar channel activity in CHO cells overexpressed with WT and I26T mutant Kir4.1/5.1 channels. In summary, this study reported a novel variant in KCNJ16, namely I26T, which is likely a benign variant and not associated with pathologic phenotype in either human or Dahl salt-sensitive rats, indicating that the type/location of variant should be considered when diagnosing and treating patients with KCNJ16 mutations.

Optimizing renal transporter immunodetection: consequences of freeze-thaw during sample preparation.

Renal transporters (cotransporters, channels, and claudins) mediate homeostasis of fluids and electrolytes and are targets of hormonal and therapeutic regulators. Assessing renal transporter abundance with antibody probes by immunoblotting is an essential tool for mechanistic studies. Although journals require authors to demonstrate antibody specificity, there are no consensus guidelines for kidney sample preparation leading to lab-to-lab variability in immunoblot results. In this study, we determined the impact of sample preparation, specifically freeze-thawed (Frozen) versus freshly processed (Fresh) kidneys (female and male rats and mice) on immunoblot signal detection of 15 renal transporters and the impact of protease inhibitors during homogenization. In female Sprague-Dawley rat kidneys homogenized with aprotinin, Na2EDTA, PMSF, and phosphatase inhibitors, immunodetection signals were ∼50% lower in Frozen versus Fresh samples for most transporters. Inclusion of additional inhibitors (Roche cOmplete Protease Inhibitor, "+") only partially increased transporter immunoblot signals to near Fresh levels. In male Sprague-Dawley rats, immunoblot signal density was lower in Frozen+ versus Fresh+ despite additional inhibitors. In C57BL/6 male mice, immunoblot signals from proximal tubule transporters were lower in Frozen versus Fresh by ∼25-50% and greater in Frozen+. In contrast, immunodetection signal was equivalent in female Frozen+ versus female Fresh+ for claudin 2, villin, AQP1, NKCC2, NCC, ENaCβ, ENaCɣ, claudin 7, AQP2, NKAα1, and NKAβ1. Thus, kidney sample preparation variables, including freeze-thaw and protease inhibition, have substantial transporter-specific effects on quantification of renal transporter abundance by immunoblot. These findings underscore the critical importance of assessing and reporting the impact of sample preparation protocols on transporter recovery to ensure robust rigor and reproducibility. NEW & NOTEWORTHY Freeze-thawing kidneys before homogenization is widely accepted in renal research. This study demonstrates that if kidneys are freeze-thawed just once before homogenization, immunoblot signals are reduced in a transporter-specific manner in rats and mice dependent on sex and that immunoblot signals can be partially recovered by adding additional protease inhibitors. These findings underscore the critical importance of assessing the impact of sample preparation, including freeze-thaw versus fresh, to ensure robust rigor and reproducibility.

Management of protective lung ventilation in children with a critical course of acute respiratory distress syndrome caused by SARS-CoV-2 coronavirus infection

the pandemic of coronavirus disease COVID-19 has created a serious threat to the public health system worldwide. With the beginning of the pandemic, it became clear that children infected by SARS-CoV-2, for unknown reasons, have a milder course compared to adults. In some cases, children are asymptomatic carriers of the infection. In light of today's scientific discoveries, contrary to initial reports, recent studies have shown that children are just as likely to contract the virus as adults, while vague symptoms and a milder course more often characterize the disease itself. However, it is worth noting that the true prevalence of asymptomatic SARS-CoV-2 infection is most likely underestimated since children are not tested for COVID-19 without obvious clinical symptoms. This fact has been confirmed by multiple blood tests indicating high titers of IgG to SARS-CoV-2. Compared to adults, the typical clinical manifestations of COVID-19 in children are fever, runny nose, cough, and general weakness. The laboratory test results indicate a normal level of leukocytes, lymphopenia, and an increased level of aspartate aminotransferase, alanine aminotransferase, D-dimer, and MB creatine kinase. Currently, there is no sufficient evidence that the etiotropic therapy is 100% successful. Yet a course of action such as respiratory system protection, control of fluids and electrolyte homeostasis, anti-cytokine therapy, preventative measures for thrombosis, and treatment for bacterial superinfection proved to be efficient at preventing the development of possible complications caused by SARS-CoV-2. Therefore, it is important to collect and accumulate new experiences\cases of respiratory system protection management of an acute respiratory syndrome with a critical course of acute respiratory distress syndrome caused by COVID-19 and implement practical treatment plans for healthcare facilities. The results were analyzed using clinical epidemiology methods. Children were admitted to the intensive care unit on an average of 6,6±0,62 days of illness and were more associated with systemic disorders and water-electrolyte imbalance, which required prosthetic respiratory function, correction of hemodynamics and water-electrolyte disorders, which was carried out in the infectious diseases department of anesthesiology and intensive care for an average of 5,2±0,7 days. In children in the clinical group, SARS-CoV-2 was verified by reverse transcription polymerase chain reaction of a nasopharyngeal swab and/or exhaled air condensate based on its positive results. Comprehensive treatment of patients with severe and extremely severe respiratory distress syndrome in coronavirus disease included respiratory and hemodynamic support, antiviral and antibacterial therapy, parenteral glucocorticosteroids and anticoagulants, which was in line with current national regulatory guidelines and local protocols. According to the criteria for choosing a method of respiratory function prosthetics, in more than half of the patients (62,2%) with hemoglobin oxygen saturation of less than 92%, while maintaining active respiratory capacity, respiratory support was provided by supplementing humidified oxygen through a face mask or nasal cannulas. In another 29,7% of patients, non-invasive ventilation was performed by constant positive airway pressure, with an oxygenation index of 0,4-0,5 and a positive end-expiratory pressure of 4-5 cm of water column. Children who had a critical course of acute respiratory syndrome caused by coronavirus infection COVID-19 (8,1%) and in whom non-invasive methods of respiratory support did not bring the desired therapeutic result were on invasive ventilation in the mode of auxiliary controlled ventilation or in the mode of synchronized intermittent forced ventilation. It should be noted that children who received respiratory support in the form of non-invasive ventilation by means of constant positive airway pressure required a lower concentration of oxygen in the inhalation mixture compared to patients on free-flow oxygen supplementation. The need for admission to the intensive care unit of children with COVID-19 is primarily associated with respiratory disorders caused by interstitial pneumonia. Oxygen supplementation was of paramount importance in patient management, primarily through noninvasive ventilation with constant positive airway pressure or free flow. The use of a pulmonary protective strategy in the treatment of acute respiratory distress syndrome caused by coronavirus disease COVID-19 in children requiring invasive ventilation was accompanied by a pronounced positive result, as it was not accompanied by side effects and resulted in a rapid recovery of patients.

The Effect of Tolvaptan on Metabolism and Electrolyte Homeostasis in Patients with Heart Failure: A Systematic Review and Meta-Analysis.

This study aimed to investigate the effect of tolvaptan on metabolism and electrolyte homeostasis in patients with heart failure (HF). Literature databases, such as PubMed, EMBASE, the Cochrane Library, China National Knowledge Infrastructure, VIP, and WanFang Data, were systematically searched for relevant trials from inception to November 4, 2023. We used the fixed effect model to combine the effect sizes and used I2 to test heterogeneity. Funnel plots were plotted to assess publication bias. 16 studies were eligible for further analysis. No significant differences were identified in the incidence of hyperuricemia between the tolvaptan group and the placebo group (odds ratio (OR) = 1.23, 95% confidence interval (CI) = 0.97 to 1.55, p = 0.09). Tolvaptan decreased the levels of blood uric acid compared to traditional diuretics (mean difference (MD) = -82.8, 95% CI = -96.48 to -69.13, p < 0.00001). There was no significant difference in hypernatremia (OR = 1.62, 95% CI = 0.66 to 3.96, p = 0.29) and hyperkalemia (OR = 1.17, 95% CI = 0.93 to 1.48, p = 0.18) between the tolvaptan and control groups. Tolvaptan reduced the level of blood uric acid compared to conventional diuretics, and could be used as a substitute for traditional diuretics for HF patients with a high risk of gout.

Inhibition of WNK Kinases in NK Cells Disrupts Cellular Osmoregulation and Control of Tumor Metastasis

Introduction: The serine/threonine with-no-lysine (WNK) kinase family function in blood pressure control, electrolyte homeostasis, and cellular osmoregulation. These kinases and their downstream effectors are considered promising therapeutic targets in hypertension and stroke. However, the role of WNK kinases in immune cells remains poorly understood. Methods: Using the small-molecule WNK kinase inhibitors WNK463 and WNK-IN-11, we investigated how WNK kinase inhibition affects natural killer (NK) cell physiology. Results: WNK kinase inhibition with WNK463 or WNK-IN-11 significantly decreased IL-2-activated NK cell volume, motility, and cytolytic activity. Treatment of NK cells with these inhibitors induced autophagy by activating AMPK and inhibiting mTOR signaling. Moreover, WNK kinase inhibition increased phosphorylation of Akt and c-Myc by misaligning activity of activating kinases and inhibitory phosphatases. Treatment of tumor-bearing mice with WNK463 impaired tumor metastasis control by adoptively transferred NK cells. Conclusion: The catalytic activity of WNK kinases has a critical role of multiple aspects of NK cell physiology and their pharmacologic inhibition negatively impacts NK cell function.

A Possible Link between Cell Plasticity and Renin Expression in the Collecting Duct: A Narrative Review.

The hormone renin is produced in the kidney by the juxtaglomerular cells. It is the rate-limiting factor in the circulating renin-angiotensin-aldosterone system (RAAS), which contributes to electrolyte, water, and blood pressure homeostasis. In the kidneys, the distal tubule and the collecting duct are the key target segments for RAAS. The collecting duct is important for urine production and also for salt, water, and acid-base homeostasis. The critical functional role of the collecting duct is mediated by the principal and the intercalated cells and is regulated by different hormones like aldosterone and vasopressin. The collecting duct is not only a target for hormones but also a place of hormone production. It is accepted that renin is produced in the collecting duct at a low level. Several studies have described that the cells in the collecting duct exhibit plasticity properties because the ratio of principal to intercalated cells can change under specific circumstances. This narrative review focuses on two aspects of the collecting duct that remain somehow aside from mainstream research, namely the cell plasticity and the renin expression. We discuss the link between these collecting duct features, which we see as a promising area for future research given recent findings.

Effect of the competitive exclusion culture on the growth, blood parameters, leg health, and innate immunity of broiler chickens

Abstract The primary aim of poultry production is to obtain a high yield and quality end product. To reduce the risk of disease, many direct-fed microbial products have been developed. That appears to be an excellent tool for disease prevention. We evaluated the influence of the commercial, competitive exclusion (CE) product, Broilact®, on the growth rate, hematology, serum biochemistry, and innate immunity in male ROSS-308 chickens, randomly divided into two groups (Broilact® treatment and control) raised for 42 days. The birds’ body weight was determined at 1, 7, 14, 28, 35, and 42 days, and the blood samples were collected at days 22 and 42 of life. We observed lower mortality, better gait score, and higher final body weight in the Broilact® group. At day 22, birds from the treated group presented higher white blood cells counts (WBC) and T cytotoxic lymphocyte (CD8+) counts, higher total protein (TP) (fraction globulin and albumin), and lower triglyceride (TAG) and Ca2+ plasma concentrations. No differences were found in acute phase proteins (APPs). At day 42, only the K+ and Na+ concentrations were higher, while the IL-10 was lower in treated birds’ blood serum. Our results indicate that treatment with one dose of the Broilact® product at day one of life has a beneficial influence, which improves the chickens’ performance, leg health and some serum enzymes activity, maintains electrolyte homeostasis, and influences leukocyte count with the rise of T CD8+ subpopulations.

Abstract P435: PROTEIN KINASE MODULATION IN THE INVESTIGATION OF ANGIOTENSIN-CONVERTING ENZYME AS A SIGNALING PATHWAY.

The Renin-Angiotensin System (RAS) is a hormonal cascade intricately involved in regulating hydro electrolyte homeostasis and blood pressure control. The Angiotensin II peptide (ANGII) is the main and most potent biologically active product within this system, which is produced by the action of Angiotensin Converting Enzyme (ACE) on Angiotensin I. Dysregulation of the RAS is an important factor in the pathogenesis and progression of cardiovascular diseases and diabetes. Furthermore, ACE inhibitors (iECA) havebeen associated with the activation of signaling pathways, thus implicating ACE as a signal transducer molecule. This study aims to elucidate the significance of signaling pathways triggered by ACE and proteins that are differentially regulated when CHO-ECA cells are stimulated with ACE inhibitors. At approximately 80% confluency, the cells were deprived of serum and then stimulated with captopril (1μM) or enalapril (1μM) or vehicle for 2 and 5 minutes (n=10 in each group), to discerning the influence of sulfhydryl and carboxyl radicals. CHO-ECA cells were cultured for Kinase Array assay analysis using the Phospho-kinase Array Kit. This assay demonstrated that some pathways were positively modulated after captopril treatment after 2 minutes (AMPKa1, HSP27, Akt 1/2/3 T308) and after 5 (STATa/b, HSP60, b-Catenin). Some kinases were negatively modulated by captopril treatment (p53, PLC-γ1, Pyk2, eNOS). Conversely, treatment with enalapril modulated proteins differently at both treatment times. Some phospho-protein kinases were positively modulated in 2 minutes, such as PLC γ1, PYK2, and Yes, and others were positively modulated in 5 minutes (EGFR, GSK-3α/β, Lyn, PDGF Rβ, STAT 5a/b, WNK1 and STAT3 S2). The kinases AKT 1/2/3 T308, AKT 1/2/3 S743, CREB, Chk-2, c-Jun, JNK1/2/3, Lck, p38α, STAT3 Y705, β-Catenin were positively modulated in 2 and 5 minutes. The kinases eNOS, ERK1/2, GSK-3β, HSP27, p53 S15, p53 S46, MSK1/2, p70 S6 T389, p70 S6 T421/S424, PRAS40, Src, RSK1/2, RSK1/2/3, STAT1 and HSP60 were negatively modulated at 2 and 5 minutes. In conclusion, our findings augmented the current understanding of kinases modulated by captopril or enalapril, after ACE binding, highlighting the multifaceted role of ACE. Therefore, it can suggest that ACE may be a candidate to act not only as an enzyme but also as a signaling receptor and transducer protein.

Advanced progress of the relationship between renin-angiotensin-aldosterone system inhibitors and cancers.

Hypertension and cancers are the most common causes of death in humans, as well as common co-diseases among elderly population. Studies have shown that hypertension is associated with carcinogenesis. The renin-angiotensin-aldosterone system (RAAS) is a crucial regulatory system of blood pressure, fluid, and electrolyte homeostasis, which plays an essential role in the pathogenesis of hypertension, whose mechanism is relatively clear. Studies have indicated that RAAS also widely exists in cancer tissues of different systems, which can affect the risk of cancers by stimulating cancer angiogenesis, participating in cancer-related oxidative stress, and regulating cancer-related immunity. Therefore, inhibiting RAAS activity seems beneficial to decreasing the risk of cancers. As one of the most commonly used antihypertensive drugs, RAAS inhibitors have been widely used in clinical practice. However, the conclusions of clinical studies on the relationship between RAAS inhibitors and cancers are not entirely consistent, which has been widely concerned by clinicians. The latest findings suggest that while RAAS inhibitors may reduce the risk of digestive cancers, respiratory cancers, urological cancers, gynecological cancers, and skin cancers, ACEIs may increase the risk of lung cancer, endometrial cancer, basal cell carcinoma, and squamous cell carcinoma. This article comprehensively reviews animal experiments, clinical studies, and meta-analyses on the relationship between RAAS inhibitors and cancers, to provide references for related studies in the future.

Incidence and predictors of acute kidney injury among asphyxiated neonates in comprehensive specialized hospitals, northwest Ethiopia, 2023

Acute kidney injury (AKI) is characterized by a sudden decline in the kidneys' abilities to remove waste products and maintain water and electrolyte homeostasis. This study aims to determine the incidence and predictors of acute kidney injury among neonates with perinatal asphyxia admitted at the neonatal intensive care unit of West Amhara Comprehensive Specialized Hospital, Northwest Ethiopia, 2023. Multicentred institution-based retrospective follow-up study was conducted from October 1, 2021, to September 30, 2023, among 421 perinatal asphyxia neonates. A simple random sampling technique was used. The data were collected using a data extraction checklist from the medical registry of neonates. The collected data were entered into EPI-DATA V.4.6.0.0. and analyzed using STATA V.14. The Kaplan–Meier failure curve and log-rank test were employed. Bivariable and multivariable Cox regression was carried out to identify predictors of Acute kidney injury. Statistical significance was declared at a p ≤ 0.05. The overall incidence of AKI was 54 (95% CI 47.07–62.51) per 100 neonate days. C/S delivery (AHR = 0.64; (95% CI 0.43–0.94), prolonged labor (AHR = 1.43; 95% CI 1.03–1.99) low-birth weight times (AHR = 1.49; (95% CI 1.01–2.20), stage three HIE(AHR: 1.68; (95% CI (1.02–2.77), No ANC follow up (AHR = 1.43; 95% CI 1.9 (1.07–3.43) and Hyperkalemia (AHR = 1.56; 95% CI 1.56 (1.05–2.29); 95% CI) were significant predictors. The incidence rate of acute kidney injury was higher than in other studies conducted on other groups of neonates. Cesarean section delivery, prolonged low birthweight, no Anc follow-up, stage 3 HIE, and neonatal hyperkalemia were predictors of acute kidney injury. However, it needs further prospective study. Therefore, the concerned stakeholders should give due attention and appropriate intervention to these predictors.

Electrolyte disruption in drug-resistant tuberculosis: Managing risks for improved treatment outcomes

This editorial sheds light on the critical issue of electrolyte imbalance in drug-resistant tuberculosis (TB), a significant challenge exacerbated by the prolonged and intensive treatment regimens required for multidrug-resistant (MDR) and extensively drug-resistant (XDR) TB strains. The use of second-line drugs, such as fluoroquinolones and aminoglycosides, necessary in these cases, often disrupts electrolyte homeostasis, leading to complications like hypokalemia and hypomagnesaemia. These disturbances can pose serious risks to patients, including cardiac arrhythmias and renal dysfunction. Beyond medication effects, TB itself induces systemic inflammation and metabolic alterations, further complicating electrolyte balance. Effective management necessitates vigilant monitoring of electrolyte levels throughout treatment, coupled with renal function assessments and nutritional support.

Anthropogenic events and responses to environmental stress are shaping the genomes of Ethiopian indigenous goats

Anthropological and biophysical processes have shaped livestock genomes over Millenia and can explain their current geographic distribution and genetic divergence. We analyzed 57 Ethiopian indigenous domestic goat genomes alongside 67 equivalents of east, west, and north-west African, European, South Asian, Middle East, and wild Bezoar goats. Cluster, ADMIXTURE (K = 4) and phylogenetic analysis revealed four genetic groups comprising African, European, South Asian, and wild Bezoar goats. The Middle Eastern goats had an admixed genome of these four genetic groups. At K = 5, the West African Dwarf and Moroccan goats were separated from East African goats demonstrating a likely historical legacy of goat arrival and dispersal into Africa via the coastal Mediterranean Sea and the Horn of Africa. FST, XP-EHH, and Hp analysis revealed signatures of selection in Ethiopian goats overlaying genes for thermo-sensitivity, oxidative stress response, high-altitude hypoxic adaptation, reproductive fitness, pathogen defence, immunity, pigmentation, DNA repair, modulation of renal function and integrated fluid and electrolyte homeostasis. Notable examples include TRPV1 (a nociception gene); PTPMT1 (a critical hypoxia survival gene); RETREG (a regulator of reticulophagy during starvation), and WNK4 (a molecular switch for osmoregulation). These results suggest that human-mediated translocations and adaptation to contrasting environments are shaping indigenous African goat genomes.