Regulation Of Fluid Volume Research Articles

Renal denervation: a key approach to hypertension and cardiovascular disease.

Sympathetic activation plays a critical role in the development of hypertension and cardiovascular disease, including heart failure and arrhythmias. Renal nerves contribute to the regulation of blood pressure and fluid volume through renal sympathetic efferent nerves, and to the modulation of sympathetic outflow through renal sensory afferent nerves. Previous studies including ours suggest that selective afferent renal denervation with preservation of efferent renal nerves can significantly decrease central sympathetic outflow in animal models of hypertension with renal damage. In Dahl salt-sensitive rats fed high salt diet from an early age, a model of hypertensive heart failure, this central sympathoinhibition by afferent renal denervation may attenuate the development of heart failure without significant blood pressure reduction. Accumulating clinical evidence supports the efficacy of renal denervation as an antihypertensive treatment. However, it remains important to clarify the appropriate indications and predictors of responders to renal denervation in the treatment of hypertension. Several clinical studies suggest beneficial effects of renal denervation in patients with heart disease, with or without hypertension, although most were not sham-controlled. In particular, some clinical studies have demonstrated that renal denervation reduces the incidence of atrial fibrillation or cardiovascular events even without a significant antihypertensive effect. It is essential to accumulate more insightful data in patients undergoing renal denervation, to establish the efficacy of renal denervation in patients with cardiovascular disease in the clinical setting, and to elucidate the therapeutic mechanisms of renal denervation and the renal nerves-linked pathophysiology of cardiovascular disease in basic research. This review outlines the effects of renal denervation on sympathetic activity and organ damage in animal models of hypertension and hypertensive heart failure, including our own data. Beyond the antihypertensive effects, the beneficial effects of renal denervation on cardiovascular disease are also discussed based on clinical studies. Several animal and clinical studies suggest the cardioprotective effects of renal denervation even in the absence of significant blood pressure reduction, probably due to its sympathoinhibitory effects.

Renal denervation for resistant hypertension in an elderly patient despite quintuple antihypertensive therapy: a case report

Hypertension is the leading cause of cardiovascular morbidity and mortality. Renal nerves have critical roles in the regulation of blood pressure and fluid volume, and their dysfunction is closely associated with cardiovascular diseases. The denervation procedure is performed through a renal ablation catheter and has been shown in recent trials to provide impressive blood pressure reductions and a favorable safety profile in drug-resistant hypertension. We present a 78-year-old patient who underwent renal denervation due to unresponse to quintuple antihypertensive treatment.

Erythropoiesis and estimated fluid volume regulation following initiation of ipragliflozin treatment in patients with type 2 diabetes mellitus and chronic kidney disease: A post-hoc analysis of the PROCEED trial.

To analyse the changes in erythropoietic and estimated fluid volume parameters after the initiation of ipragliflozin, a sodium-glucose co-transporter 2 inhibitor, in patients with type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD). This was a post-hoc analysis of the PROCEED trial, which evaluated the effect of 24-week ipragliflozin treatment on endothelial dysfunction in patients with T2DM and CKD. We evaluated the changes in erythropoietic and estimated fluid volume parameters from baseline to 24 weeks post-treatment in 53 patients who received ipragliflozin (ipragliflozin group) and 55 patients with T2DM and CKD without sodium-glucose co-transporter 2 inhibitors (control group), a full analysis set of the PROCEED trial. The increases in haemoglobin [estimated group difference, 0.5 g/dl; 95% confidence interval (CI), 0.3-0.8; p < .001], haematocrit (estimated group difference, 2.2%; 95% CI, 1.3-3.1; p < .001) and erythropoietin (estimated log-transformed group difference, 0.1; 95% CI, 0.01-0.3; p = .036) were significantly greater in the ipragliflozin group than those in the control group. Ipragliflozin treatment was significantly associated with an increase in erythropoietin, independent of the corresponding change in haemoglobin (β = 0.253, p < .001) or haematocrit (β = 0.278, p < .001). Reductions in estimated plasma volume (estimated group difference, -7.94%; 95% CI, -11.6 to -4.26%; p < .001) and estimated extracellular volume (estimated group difference, -181.6 ml; 95% CI, -275.7 to -87.48 ml; p < .001) were significantly greater in the ipragliflozin group than those in the control group. Erythropoiesis was enhanced and estimated fluid volumes were reduced by ipragliflozin in patients with T2DM and CKD. PROCEED trial (registration number: jRCTs071190054).

Natriuretic Peptide Receptors (NPRs) as a Potential Target for the Treatment of Heart Failure.

Heart failure is defined as a complex clinical syndrome that results from any structural or functional impairment of ventricular filling or ejection of blood. The natriuretic peptide is known to exert its biological action on the kidney, heart, blood vessels, renin-angiotensin system, autonomous nervous system, and central nervous system. The natriuretic peptide-natriuretic receptor system plays an important role in the regulation of blood pressure and body fluid volume through its pleiotropic effects. The clinical and animal studies suggest that natriuretic peptide-natriuretic receptors are important targets for the treatment of heart failure and other cardiovascular diseases. Even though attempts targeting natriuretic peptide receptors are underway for heart failure treatment, they seem insufficient despite the receptor systems' potential. This review summarizes natriuretic peptide-natriuretic receptor system's physiological actions and potential target for the treatment of heart failure. Natriuretic peptides play multiple roles in different parts of the body, almost all of the activities related to this receptor system appear to have the potential to be harnessed to treat heart failure or symptoms associated with heart failure.

Role of Vena Cava Inferior Ultrasound in Volume Assesment

Regulation of body fluid volume is a key concern for physicians in intensive care units. In intensive care, it is most important to determine the intracellular fluid status because it directly affects the volume status of the patient. Ultrasonography appears to be a useful tool for the assessment of body fluid status. The gold standard for measuring central venous pressure (CVP) is a central venous catheter. Vena cava inferior ultrasound (US-VCI) has been proposed as the non-invasive technique of choice for CVP assessment due to its wide availability, low costs, and ease of use. While a depleted IVC is often observed in hypovolemic patients, typically the IVC is dilated in a hypervolemic condition with a less pronounced or null respiratory collapse in the appropriate clinical context. respiratory variability in VCI diameteris known as the caval index (collapsibility index=VCImaxVCImin /VCImax) and is considered to reflect the intravascular volume state. According to the current updated American and European guidelines, an IVC diameter ≤2.1 cm and collapsibility &gt;50% during inspiration suggest a RAP between 0–5 mm Hg while a diameter &gt;2.1 cm with &lt;50% inspiratory collapse indicates a high RAP of 10–20 mmHg. Primarily because of complicated pathophysiological mechanisms, ultrasound measurement of VCI should not be used as the only parameter in the assessment of volemic status.

Age and sex variations in serum brain natriuretic peptide level following doxorubicin-induced myocardial injury in Wistar rats

Background: Brain natriuretic peptide (BNP), a cardiac hormone produced by ventricular myocytes, plays an important role in the regulation of blood pressure and fluid volume. Although serum BNP level increases with age in normals, this response and possible sex variations in the presence of drug-induced myocardial injury need to be explored further. Methods: Twenty-four Wistar rats were separated into two groups, the controls and doxorubicin-myocardial injury (DOX-MI) model group. Each group was further subdivided into aged (100–104 weeks) and young (13–14 weeks), having an equal number of males and females (n = 3). The DOX-MI Model group was given 2.5 mg/kg DOX through intra-peritoneal injection on alternate days to a cumulative dose of 12.5 mg/kg. Blood samples were then collected and centrifuged at 3000 g for 15 min and serum BNP analysis was conducted using BNP ELISA Kit (BIOTUVA LIFE SCIENCES, UK). Results: BNP was significantly lower (P = 0.003) in the aged (100–104 weeks) DOX-MI-model group compared to aged controls. Similarly, it was lower in the young (13–14 weeks) DOX-MI-Model group than the young controls, but the difference was not statistically significant (P = 0.16). The analysis between aged and young rats within each group indicated significantly higher BNP levels in the aged rats compared to the young in both groups (P = 0.01 for aged vs. young DOX-MI-Model and P = 0.02 for aged vs. young controls). Conclusion: DOX-induced-MI has caused a significant reduction in BNP production in the aged rats (100–104 weeks) compared to the young (13–14 weeks).

A study on etiological profile of acute kidney failure in neonates admitted to neonatal intensive care unit at a tertiary care centre

Introduction: Acute kidney failure (AKF) / Acute kidney injury (AKI) Is defined as sudden deterioration in kidney function that leads to the accumulation of nitrogenous waste products (e.g.urea) and alters the regulation of extra cellular fluid volume, electrolyte and acid-base homeostasis. Renal dysfunction due to acute kidney failure is common in high-risk newborn babies and its incidence varies depending upon the criteria used for diagnosis. Materials and Methods: A 18 months study involving all those neonates who admitted in NICU, GGH Kurnool with manifestations of acute kidney injury. The study population comprised of all the neonates suspected or diagnosed with AKF were admitted as per the inclusion and exclusion criteria’s mentioned earlier in NICU, Govt General Hospital, Kurnool between the time period of 18 months from 2019 to 2021. A detailed birth history involving resuscitation, detailed maternal history was recorded as precoded proforma was available. All the inborn deliveries were attended by the pediatric resident. Gestational age was assessed by Modified Ballard scoring system. The physical examination of the baby at the time of admission was recorded in the proforma. Sarnat and Sarnat classification was used for HIE. Results: Among 100 neonates 67 (67%) were male, 33 (33%) were female.

The Renin‐Angiotensin System after Pig Kidney Transplantation in Baboons

Resolution of many technical and immune‐related issues have allowed long‐term survival of baboons with life‐supporting pig kidney grafts. However, episodes of hypovolemia and hypotension during the post‐transplant period occur via an unexplained mechanism. It has been reported that pig renin has low reactivity on human angiotensinogen (AGT). Because the renin‐angiotensin system (RAS) is vitally important in the regulation of extracellular fluid volume and blood pressure, we evaluated the activity of the RAS in baboon’s post‐pig kidney xenotransplantation. Kidneys from genetically‐modified pigs were transplanted into 5 baboons (6 to 10 kg) that were immunosuppressed by blockade of the CD40/CD154 costimulation pathway, after excision of the native kidneys. Plasma renin, AGT (only baboon AGT could be measured), and angiotensin II levels were measured by ELISAs in (i) healthy genetically‐modified pigs (n=3), healthy non‐immunosuppressed baboons (n=6), and (iii) immunosuppressed baboons with pig kidney grafts. Samples were collected for up to 120 days post‐transplantation. Plasma renin levels were significantly greater in healthy pigs (586±139 (SE) pg/ml) than in intact baboons (430±28 pg/ml). The plasma renin levels in baboons with pig kidney grafts were similar to values in intact baboons (367±18 pg/ml), indicating the continuing production of renin by the pig kidney grafts in absence of baboon kidneys. Plasma AGT (which reflected only baboon AGT) levels were augmented in the transplanted baboons (21±0.8 µg/ml) compared to the pre‐transplant concentrations (9.9±0.8). Plasma angiotensin II levels were 16±1.3 pg/ml in intact baboons and trended lower from pre‐transplant levels in the transplanted baboons (10±1.6 pg/ml). Lower plasma angiotensin II concentrations in baboons with pig kidney grafts, even in the presence of increasing plasma AGT levels, may be a consequence of reduced, but not absent, reactivity of pig renin to cleave baboon AGT. The reduced angiotensin II levels in the transplanted baboons suggest an impaired ability to elicit a robust response to hypovolemic and hypotensive episodes.

Ceramide-1-Phosphate as a Potential Regulator of the Second Sodium Pump from Kidney Proximal Tubules by Triggering Distinct Protein Kinase Pathways in a Hierarchic Way.

Kidney proximal tubules are a key segment in the reabsorption of solutes and water from the glomerular ultrafiltrate, an essential process for maintaining homeostasis in body fluid compartments. The abundant content of Na+ in the extracellular fluid determines its importance in the regulation of extracellular fluid volume, which is particularly important for different physiological processes including blood pressure control. Basolateral membranes of proximal tubule cells have the classic Na+ + K+-ATPase and the ouabain-insensitive, K+-insensitive, and furosemide-sensitive Na+-ATPase, which participate in the active Na+ reabsorption. Here, we show that nanomolar concentrations of ceramide-1 phosphate (C1P), a bioactive sphingolipid derived in biological membranes from different metabolic pathways, promotes a strong inhibitory effect on the Na+-ATPase activity (C1P50 ≈ 10 nM), leading to a 72% inhibition of the second sodium pump in the basolateral membranes. Ceramide-1-phosphate directly modulates protein kinase A and protein kinase C, which are known to be involved in the modulation of ion transporters including the renal Na+-ATPase. Conversely, we did not observe any effect on the Na+ + K+-ATPase even at a broad C1P concentration range. The significant effect of ceramide-1-phosphate revealed a new potent physiological and pathophysiological modulator for the Na+-ATPase, participating in the regulatory network involving glycero- and sphingolipids present in the basolateral membranes of kidney tubule cells.

Correlation of amniotic fluid index and placental aquaporin 1 levels in terms of preeclampsia.

Aquaporin 1 (AQP1) plays an important role in regulation of maternal-fetal fluid exchange and amniotic fluid volume. This present study aimed to determine the relationship between amniotic fluid index and placental AQP1 levels in terms of preeclampsia, and to reveal possible pathophysiological changes of AQP1 expression under preeclamptic conditions. Placental tissues and medical records information were obtained from 389 preeclamptic and 447 uncomplicated pregnancies. Placental AQP1 levels were analyzed by molecular biological methods, DNA methylation within gene promotor was determined by targeted bisulfite sequencing assay. Here, we found that preeclamptic pregnancy had a greater frequency of oligohydramnios, and higher placental AQP1 levels. There was a significantly inverse correlation between amniotic fluid index and placental AQP1 levels in preeclampsia cases. Additionally, the increased AQP1 was correlated with a decreased DNA methylation within its gene promoter. Overall, this was the first description that a greater frequency of oligohydramnios in preeclampsia was strongly associated with reprogrammed AQP1 expression via a DNA methylation-mediated epigenetic mechanism. This study suggested AQP1 might play an important role in regulating maternal-fetal fluid balance under preeclamptic conditions, providing new information for further understanding the pathophysiological mechanism of oligohydramnios in preeclampsia.

Anatomophysiology of the Henle's Loop: Emphasis on the Thick Ascending Limb.

The loop of Henle plays a variety of important physiological roles through the concerted actions of ion transport systems in both its apical and basolateral membranes. It is involved most notably in extracellular fluid volume and blood pressure regulation as well as Ca2+ , Mg2+ , and acid-base homeostasis because of its ability to reclaim a large fraction of the ultrafiltered solute load. This nephron segment is also involved in urinary concentration by energizing several of the steps that are required to generate a gradient of increasing osmolality from cortex to medulla. Another important role of the loop of Henle is to sustain a process known as tubuloglomerular feedback through the presence of specialized renal tubular cells that lie next to the juxtaglomerular arterioles. This article aims at describing these physiological roles and at discussing a number of the molecular mechanisms involved. It will also report on novel findings and uncertainties regarding the realization of certain processes and on the pathophysiological consequences of perturbed salt handling by the thick ascending limb of the loop of Henle. Since its discovery 150 years ago, the loop of Henle has remained in the spotlight and is now generating further interest because of its role in the renal-sparing effect of SGLT2 inhibitors. © 2022 American Physiological Society. Compr Physiol 12:1-21, 2022.

Recurrence of idiopathic polyhydramnios: A nationwide population study.

Polyhydramnios occurs in approximately 1% of pregnancies, and idiopathic polyhydramnios (IPH) manifests with an unknown cause in 40–50% of all cases.1 Elucidating whether there is a recurrence risk will add to a better and more complete understanding of IPH.2 The objective of the present study was to calculate an odds ratio (OR) for recurrence of IPH in parous women and across generations. This was achieved by utilizing data from the compulsory Medical Birth Registry of Norway (MBRN), including all singleton births between 1967 and 2017 (n = 2 741 480). The midwife or physician attending the birth clinically judged the amount of amniotic fluid and reported this (oligohydramnios, normal, or polyhydramnios) in their notification to the registry. Polyhydramnios without fetal syndromes, malformations, infections, immunization, or maternal diabetes mellitus was defined as IPH. The authors linked the subsequent births of each woman, and across generations, by using unique national identification numbers. We calculated ORs (with 95% confidence intervals [CI]) and adjusted ORs (AOR) for recurrent IPH in subsequent births and across generations using multilevel logistic regression analysis. Possible confounding factors included: maternal age, body mass index, medical conditions, parity, smoking habits, year of birth, birthweight, placental weight, and sex of the neonate. The Regional Ethics Committee (2013/1484) and the registry owners provided ethical approval for the study protocol. SPSS version 26 (IBM Corp.) and MLwiN version 3.05 was used for analysis. IPH occurred in 0.6% of births and increased in incidence during the study period in question (0.4–1.1%). Women with a history of IPH in the first pregnancy had a seven-fold risk of IPH in the second pregnancy (Table 1). The OR of recurrence in subsequent births increased according to IPH status in the previous births. The OR of inter-generational recurrence was three-fold. Including the year of birth in the model attenuated the risk of recurrence, while including maternal or pregnancy factors did not significantly alter the results, and, therefore, were not included in the final model. A sensitivity-analysis, performed with Bayesian regression, suggested that recurrence of IPH was robust for unknown confounding factors. IPH tended to recur in subsequent births in a dose-response pattern according to history of IPH, and between generations, suggesting an influence of hereditary and/or sustained environmental factors in the regulation of amniotic fluid volume. Although validation studies have shown that the MBRN holds high quality data and is suitable for epidemiological research,3 the clinical variables describing amniotic fluid volume remains to be validated. The strengths of the present study are its prospective data collection, the population-based design, and essentially complete record linkage. The Medical Birth Registry of Norway for providing the datafile. The authors have no conflicts of interest. SR contributed to the study methodology, data curation, validation, manuscript drafting, review and editing of the manuscript, and study supervision. LL was responsible for the study methodology, data curation, formal analysis, drafting of the manuscript, and review and editing of the manuscript. CE contributed to the study conceptualization, methodology, formal analysis, project administration, writing of the original draft of the manuscript, and review and editing of the manuscript. All authors contributed to and approved of the version of the manuscript to be published.

Estrogen to Progesterone Ratio and Fluid Regulatory Responses to Varying Degrees and Methods of Dehydration

The purpose of this study was to investigate the relationship between volume regulatory biomarkers and the estrogen to progesterone ratio (E:P) prior to and following varying methods and degrees of dehydration. Ten women (20 ± 1 year, 56.98 ± 7.25 kg, 164 ± 6 cm, 39.59 ± 2.96 mL•kg•min−1) completed four intermittent exercise trials (1.5 h, 33.8 ± 1.3°C, 49.5 ± 4.3% relative humidity). Testing took place in two hydration conditions, dehydrated via 24-h fluid restriction (Dehy, USG > 1.020) and euhydrated (Euhy, USG ≤ 1.020), and in two phases of the menstrual cycle, the late follicular phase (days 10–13) and midluteal phase (days 18–22). Change in body mass (%BMΔ), serum copeptin concentration, and plasma osmolality (Posm) were assessed before and after both dehydration stimuli (24-h fluid restriction and exercise heat stress). Serum estrogen and progesterone were analyzed pre-exercise only. Estrogen concentration did not differ between phases or hydration conditions. Progesterone was significantly elevated in luteal compared to follicular in both hydration conditions (Dehy—follicular: 1.156 ± 0.31, luteal: 5.190 ± 1.56 ng•mL−1, P < 0.05; Euhy—follicular: 0.915 ± 0.18, luteal: 4.498 ± 1.38 ng·mL−1, P < 0.05). As expected, E:P was significantly greater in the follicular phase compared to luteal in both hydration conditions (Dehy—F:138.94 ± 89.59, L: 64.22 ± 84.55, P < 0.01; Euhy—F:158.13 ± 70.15, L: 50.98 ± 39.69, P < 0.01, [all •103]). Copeptin concentration was increased following 24-h fluid restriction and exercise heat stress (mean change: 18 ± 9.4, P < 0.01). We observed a possible relationship of lower E:P and higher copeptin concentration following 24-h fluid restriction (r = −0.35, P = 0.054). While these results did not reach the level of statistical significance, these data suggest that the differing E:P ratio may alter fluid volume regulation during low levels of dehydration but have no apparent impact after dehydrating exercise in the heat.

Renal Function Impairment and Associated Factors Among Adult HIV-Positive Patients Attending Antiretroviral Therapy Clinic in Mettu Karl Referral Hospital: Cross-Sectional Study.

BackgroundHuman immunodeficiency virus (HIV) affects every organ system in the body through impairment or by rendering the patient vulnerable to opportunistic infections. The kidney is the vital organ in the excretion of waste products and toxins (urea, creatinine and uric acid), and regulation of extracellular fluid volume, serum osmolality and electrolyte concentrations. The risk of kidney disease is greater in HIV-infected individuals than in the general population. This study aimed to assess the magnitude of renal function impairment and its associated factors among adult HIV-positive patients attending an ART clinic in Mettu Karl Referral Hospital, Mettu town, south-west Ethiopia.MethodsThe institution-based, cross-sectional quantitative study was conducted from March 8 to May 30, 2020. A total of 352 clients participated and a systematic sampling technique was used to allocate study participants. Data were entered into Epi data and exported to SPSS version 22 for analysis. Bivariate analysis was conducted to identify candidate variables for multivariate analysis at P <0.25. Multivariable logistic regression analysis was conducted to determine the predictors of renal function impairment with ART. P value < 0.05 was considered to indicate statistical significance.ResultsA total of 352 HIV-infected patients participated in this study with a response rate of 98.1%. Out of 352 HIV patients on ART, 73 (20.7%) were found to have renal function impairment. Cigarette smoking [AOR = 9.60, 95% CI: 4.73–19.48], diabetes mellitus [AOR = 6.16, 95% CI: 2.79–13.59], hypertension [AOR = 4.71, 95% CI: 1.98–11.17] and low CD4 count [AOR = 6.47, 95% CI: 3.31–12.64] were found to be independent predictors of renal function impairment among adult HIV positive patients.ConclusionThe prevalence of renal function impairment among HIV patients on ART is high. Hypertension, diabetes, cigarette smoking and low CD4 count were associated factors of renal function impairment. HIV patients on ART should be regularly screened for early diagnosis and management of renal function impairment.

Correlation of Amniotic Fluid Index and Placental Aquaporin 1 Levels in Terms of Preeclampsia

Background: Aquaporin 1 (AQP1) plays an important role in regulation of maternal-fetal fluid exchange and amniotic fluid volume. This present study aimed to determine the relationship between amniotic fluid index and placental AQP1 levels in terms of preeclampsia, as well as to reveal possible pathophysiological changes of AQP1 expression under preeclamptic conditions. Methods: Placenta tissues and medical records information were obtained from 389 preeclamptic and 447 uncomplicated pregnancies. Placental AQP1 levels were analyzed by molecular biological methods, DNA methylation in AQP1 gene promotor was determined by targeted bisulfite sequencing assay. Findings: Preeclamptic pregnancy had a greater frequency of oligohydramnios, and higher placental AQP1 levels. There was a significantly inverse correlation between amniotic fluid index and AQP1 levels in preeclamptic placenta. Additionally, the increased AQP1 was correlated with a decreased DNA methylation within the gene promoter. Interpretation:This study was the first description that a greater frequency of oligohydramnios in preeclampsia was strongly associated with reprogrammed AQP1 expression via a DNA methylation-mediated epigenetic mechanism. This study indicated an important role of AQP1-mediated maternal-fetal fluid balance and provided a potential direction for the identification of therapeutic targets for the treatment of abnormalities in preeclamptic amniotic fluid volume. Funding: This study was supported partly by Ministry of Science and Technology of China (2019YFA0802600), National Nature & Science Foundation of China (81873841, 81741024, and 81401244), “333 Project”, “Six one project (LGY2018076)”, “Shuang Chuang Tuan Dui” and Key Discipline “Fetal medicine” of Jiangsu Province, and the Suzhou city “Wei Sheng Ren Cai (GSWS2019029)” program. Declaration of Interest: None to declare. Ethical Approval: First Hospital of Soochow University, Suzhou, China. #302 (05/11/2015).

Modulation of Cerebrospinal Fluid Production by Transient Receptor Potential Vanilloid 4: Implications for Disorders of Brain Fluid Volume

Cerebrospinal fluid (CSF) secretion into the brain ventricular system is an active process via the choroid plexus (CP) - a specialized convoluted epithelial sheet surrounding a fenestrated capillary bed which is fed from the cerebral arterioles. The final CSF composition differs from a simple plasma filtrate implicating the CP as an important regulatory site controlling CSF composition and volume. Flux across this blood-CSF barrier is tightly controlled by ion and water transport proteins. Transient Receptor Potential Vanilloid 4 (TRPV4) is a polymodal, non-selective cation channel which functions as a regulatory hub protein in epithelia, including the CP. Our previous studies have shown that TRPV4-selective antagonists were effective at reducing ventriculomegaly in a genetic rat model of severe postnatal hydrocephalus. In CP, we found that activation of TRPV4 caused the influx of both Ca2+ and Na+ ions, and entry of both of these ions was selectively blocked by a TRPV4 antagonist. Systemic treatment with TRPV4 antagonists reduced TRPV4 mRNA expression in the CP in hydrocephalic rats, but not in normal rats, indicating a role for TRPV4 as part of a regulatory pathway in CSF production. To study the mechanism of CSF secretion by the CP, we utilized two continuous, high resistance CP cell lines: the porcine choroid plexus – Reims (PCP-R) and the human choroid plexus papilloma (HIBCPP) cells. The current experiments utilize Ussing chamber electrophysiological techniques, western blotting, qRT-PCR, and fluorescent immunolabeling. Immunolabeling and mRNA expression demonstrate a robust abundance for TRPV4 and other well-characterized CP membrane proteins in both cell lines. In both lines, TRPV4 activation stimulates a large change in short circuit current (ISC), a measure of net electrogenic ion flux. This change in ISCis coupled with a substantial change in transepithelial membrane conductance, a measure of cellular permeability. The transepithelial membrane transport changes due to TRPV4 activation in human and porcine cells are similar in overall effect, but differ in baseline, duration, and magnitude, indicating species-specific CP transport mechanisms. In both cases, these responses can be inhibited by either pre- or post-incubation with TRPV4 antagonists, substantiating the specificity to TRPV4 activation. The human cells, but not the porcine cells, demonstrate a substantial baseline transepithelial transport which is dependent on K+, Na+, and Cl- gradients. Furthermore, in both the porcine and human cells, the TRPV4 response is dependent upon K+ secretion, Cl- absorption, and Na+ secretion. These data confirm a role for TRPV4 in regulating ionic gradients, modulating both electrogenic and electroneutral transporters, and controlling CSF production. The promising results of these studies, coupled with published data from other investigators suggesting a role for TRPV4 in blood-brain-barrier permeability and astrocyte volume regulation, shows the importance of TRPV4 as a regulatory hub protein in brain fluid volume regulation.

Epithelial Sodium Channel and Salt-Sensitive Hypertension.

The development of high blood pressure is influenced by genetic and environmental factors, with high salt intake being a known environmental contributor. Humans display a spectrum of sodium-sensitivity, with some individuals displaying a significant blood pressure rise in response to increased sodium intake while others experience almost no change. These differences are, in part, attributable to genetic variation in pathways involved in sodium handling and excretion. ENaC (epithelial sodium channel) is one of the key transporters responsible for the reabsorption of sodium in the distal nephron. This channel has an important role in the regulation of extracellular fluid volume and consequently blood pressure. Herein, we review the role of ENaC in the development of salt-sensitive hypertension, and present mechanistic insights into the regulation of ENaC activity and how it may accelerate sodium-induced damage and dysfunction. We discuss the traditional role of ENaC in renal sodium reabsorption and review work addressing ENaC expression and function in the brain, vasculature, and immune cells, and how this has expanded the implications for its role in the initiation and progression of salt-sensitive hypertension.

Role of brain renin angiotensin system in neurodegeneration: An update.

Renin angiotensin system (RAS) is an endocrine system widely known for its physiological roles in electrolyte homeostasis, body fluid volume regulation and cardiovascular control in peripheral circulation. However, brain RAS is an independent form of RAS expressed locally in the brain, which is known to be involved in brain functions and disorders. There is strong evidence for a major involvement of excessive brain angiotensin converting enzyme (ACE)/Angiotensin II (Ang II)/Angiotensin type-1 receptor (AT-1R) axis in increased activation of oxidative stress, apoptosis and neuroinflammation causing neurodegeneration in several brain disorders. Numerous studies have demonstrated strong neuroprotective effects by blocking AT1R in these brain disorders. Additionally, the angiotensin converting enzyme 2 (ACE2)/Angiotensin (1–7)/Mas receptor (MASR), is another axis of brain RAS which counteracts the damaging effects of ACE/Ang II/AT1R axis on neurons in the brain. Thus, angiotensin II receptor blockers (ARBs) and activation of ACE2/Angiotensin (1–7)/MASR axis may serve as an exciting and novel method for neuroprotection in several neurodegenerative diseases. Here in this review article, we discuss the expression of RAS in the brain and highlight how altered RAS level may cause neurodegeneration. Understanding the pathophysiology of RAS and their links to neurodegeneration has enormous potential to identify potentially effective pharmacological tools to treat neurodegenerative diseases in the brain.

Analyses of epithelial Na+ channel variants reveal that an extracellular β-ball domain critically regulates ENaC gating

Epithelial Na+ channel (ENaC)-mediated Na+ transport has a key role in the regulation of extracellular fluid volume, blood pressure, and extracellular [K+]. Among the thousands of human ENaC variants, only a few exist whose functional consequences have been experimentally tested. Here, we used the Xenopus oocyte expression system to investigate the functional roles of four nonsynonymous human ENaC variants located within the β7-strand and its adjacent loop of the α-subunit extracellular β-ball domain. αR350Wβγ and αG355Rβγ channels exhibited 2.5- and 1.8-fold greater amiloride-sensitive currents than WT αβγ human ENaCs, respectively, whereas αV351Aβγ channels conducted significantly less current than WT. Currents in αH354Rβγ-expressing oocytes were similar to those expressing WT. Surface expression levels of three mutants (αR350Wβγ, αV351Aβγ, and αG355Rβγ) were similar to that of WT. However, three mutant channels (αR350Wβγ, αH354Rβγ, and αG355Rβγ) exhibited a reduced Na+ self-inhibition response. Open probability of αR350Wβγ was significantly greater than that of WT. Moreover, other Arg-350 variants, including αR350G, αR350L, and αR350Q, also had significantly increased channel activity. A direct comparison of αR350W and two previously reported gain-of-function variants revealed that αR350W increases ENaC activity similarly to αW493R, but to a much greater degree than does αC479R. Our results indicate that αR350W along with αR350G, αR350L, and αR350Q, and αG355R are novel gain-of-function variants that function as gating modifiers. The location of these multiple functional variants suggests that the αENaC β-ball domain portion that interfaces with the palm domain of βENaC critically regulates ENaC gating.

SUBCLINICAL ATHEROSCLEROSIS, SERUM URIC ACID AND PLASMA ALDOSTERONE IN HYPERTENSIVE ADULTS

Objective: aldosterone has long been classically considered to play a central role in the regulation of electrolyte and fluid volume and the maintenance of blood pressure (BP) homeostasis. Moreover, the aldosterone/mineralocorticoid system plays a key role in cardiovascular, metabolic and renal damage. This study aimed to assess the relationship between plasma aldosterone concentration (PAC) and some surrogate markers of subclinical atherosclerosis, such as carotid intima-media thickness (cIMT), ankle-brachial index (ABI) and biochemical parameters (i. e. serum uric acid – SUA, 24-h urinary albumin excretion - UAE) in subjects with essential hypertension (EH). Design and method: from January 2014 to December 2017 we consecutively enrolled 804 EH patients (407 males and 397 females, mean age 50 ± 14.5 yrs) without evident cardiovascular complications. Patients were divided in quartiles according to PAC levels. Results: Compared to the first quartile, the highest PAC quartile was associated with the highest levels of SUA (5.3 ± 1.34 vs 5.0 ± 1 mg/dl; p = 0.01) triglycerides (117.5 ± 15.7 vs 106.8 ± 10.5 mg/dl; p < 0.05), UAE (38.8 vs 17.6 mg/24ore; p < 0.05) and cIMT (0.87 ± 0.22 mm vs 0.8 ± 0.21 mm; p = 0.001). Patients of the fourth quartile also exhibited increased prevalence of carotid plaques, compared to the first quartile (26% vs. 16%; p < 0.005). Moreover, we found that in patients with PAC >160 pg/ml ABI was significantly lower compared to those with PAC < 160 pg/ml (1.01 ± 0.09 vs 1.1 ± 0.09; p < 0.022). Binary logistic regression analysis showed that PAC was an independent predictor of the presence of carotid plaques and pathological ABI (< 0.9) in the population examined. Conclusions: These findings suggest that higher values of PAC are strongly associated with higher values of SUA, triglycerides, UAE, cIMT, worse ABI and major prevalence of carotid plaques that, together with elevated BP values, are strictly correlated with higher risk of atherosclerosis and cardiovascular complications.