In the SARS-CoV-2 Pandora Pandemic: Can the Stance of Premorbid Intestinal Innate Immune System as Measured by Fecal Adnab-9 Binding of p87:Blood Ferritin, Yielding the FERAD Ratio, Predict COVID-19 Susceptibility and Survival in a Prospective Population Database?

SARS-CoV-2 severity predictions are feasible, though individual susceptibility is not. The latter prediction allows for planning vaccination strategies and the quarantine of vulnerable targets. Ironically, the innate immune response (InImS) is both an antiviral defense and the potential cause of adverse immune outcomes. The competition for iron has been recognized between both the immune system and invading pathogens and expressed in a ratio of ferritin divided by p87 (as defined by the Adnab-9 ELISA stool-binding optical density, minus the background), known as the FERAD ratio. Associations with the FERAD ratio may allow predictive modeling for the susceptibility and severity of disease. We evaluated other potential COVID-19 biomarkers prospectively. Patients with PCR+ COVID-19 tests (Group 1; n = 28) were compared to three other groups. In Group 2 (n = 36), and 13 patients displayed COVID-19-like symptoms but had negative PCR or negative antibody tests. Group 3 (n = 90) had no symptoms and were negative when routinely PCR-tested before medical procedures. Group 4 (n = 2129) comprised a pool of patients who had stool tests and symptoms, but their COVID-19 diagnoses were unknown; therefore, they were chosen to represent the general population. Twenty percent of the Group 4 patients (n = 432) had sufficient data to calculate their FERAD ratios, which were inversely correlated with the risk of COVID-19 in the future. In a case report of a neonate, we studied three biomarkers implicated in COVID-19, including p87, Src (cellular-p60-sarcoma antigen), and Abl (ABL-proto-oncogene 2). The InImS of the first two were positively correlated. An inverse correlation was found between ferritin and lysozyme in serum (p < 0.05), suggesting that iron could have impaired an important innate immune system anti-viral effector and could partially explain future COVID-19 susceptibility.

V1a and V1b vasopressin receptors within the paraventricular nucleus contribute to hypertension in male rats exposed to chronic mild unpredictable stress.

Depression is an independent nontraditional risk factor for cardiovascular disease and mortality. The chronic unpredictable mild stress (CMS) rat model is a validated model of depression. Within the paraventricular nucleus (PVN), vasopressin (VP) via V1aR and V1bR have been implicated in stress and neurocardiovascular dysregulation. We hypothesized that in conscious, unrestrained CMS rats versus control, unstressed rats, PVN VP results in elevated arterial pressure (MAP), heart rate, and renal sympathetic nerve activity (RSNA) via activation of V1aR and/or V1bR. Male rats underwent 4 wk of CMS or control conditions. They were then equipped with hemodynamic telemetry transmitters, PVN cannula, and left renal nerve electrode. V1aR or V1bR antagonism dose-dependently inhibited MAP after VP injection. V1aR or V1bR blockers at their ED50 doses did not alter baseline parameters in either control or CMS rats but attenuated the pressor response to VP microinjected into PVN by ∼50%. Combined V1aR and V1bR inhibition completely blocked the pressor response to PVN VP in control but not CMS rats. CMS rats required combined maximally inhibitory doses to block either endogenous VP within the PVN or responses to microinjected VP. Compared with unstressed control rats, CMS rats had higher plasma VP levels and greater abundance of V1aR and V1bR transcripts within PVN. Thus, the CMS rat model of depression results in higher resting MAP, heart rate, and RSNA, which can be mitigated by inhibiting vasopressinergic mechanisms involving both V1aR and V1bR within the PVN. Circulating VP may also play a role in the pressor response.

AT1 receptors in the subfornical organ modulate arterial pressure and the baroreflex in two-kidney, one-clip hypertensive rats.

The subfornical organ (SFO), a forebrain circumventricular organ that lies outside the blood-brain barrier, has been implicated in arterial pressure and baroreflex responses to angiotensin II (ANG II). We tested whether pharmacological inhibition or selective silencing of SFO ANG II type 1 receptors (AT1R) of two-kidney, one-clip rats with elevated plasma ANG II decreases resting arterial pressure and renal sympathetic nerve activity (RSNA) and/or modulates arterial baroreflex responses of heart rate (HR) and RSNA. Male Sprague-Dawley rats underwent renal artery clipping [2-kidney, 1-clip (2K,1C)] or sham clipping (sham). After 6 wk, conscious rats instrumented with vascular catheters, renal nerve electrodes, and a cannula directed to the SFO were studied. In another set of experiments, rats were instrumented with hemodynamic and nerve radio transmitters and injected with scrambled RNA or silencing RNA targeted against AT1R. Mean arterial pressure (MAP) was significantly higher in 2K,1C rats. Acute SFO injection with the AT1R inhibitor losartan did not change MAP in sham or 2K,1C rats. Baroreflex curves of HR and RSNA were shifted rightward in 2K,1C rats. Losartan exerted no effect. SFO AT1R knockdown did not influence MAP in sham rats but decreased MAP in 2K,1C rats, despite no change in plasma ANG II or resting RSNA. AT1R knockdown prevented the reduction in maximum gain and slope of baroreflex responses of HR and RSNA; the reduced RSNA response to baroreceptor unloading was partially restored in 2K,1C rats. These findings show that AT1R activation within the SFO contributes to hypertension and baroreflex dysfunction in 2K,1C rats and highlight the temporal requirement for reversal of these effects.

Regulation of blood pressure and salt homeostasis by endothelin.

Endothelin (ET) peptides and their receptors are intimately involved in the physiological control of systemic blood pressure and body Na homeostasis, exerting these effects through alterations in a host of circulating and local factors. Hormonal systems affected by ET include natriuretic peptides, aldosterone, catecholamines, and angiotensin. ET also directly regulates cardiac output, central and peripheral nervous system activity, renal Na and water excretion, systemic vascular resistance, and venous capacitance. ET regulation of these systems is often complex, sometimes involving opposing actions depending on which receptor isoform is activated, which cells are affected, and what other prevailing factors exist. A detailed understanding of this system is important; disordered regulation of the ET system is strongly associated with hypertension and dysregulated extracellular fluid volume homeostasis. In addition, ET receptor antagonists are being increasingly used for the treatment of a variety of diseases; while demonstrating benefit, these agents also have adverse effects on fluid retention that may substantially limit their clinical utility. This review provides a detailed analysis of how the ET system is involved in the control of blood pressure and Na homeostasis, focusing primarily on physiological regulation with some discussion of the role of the ET system in hypertension.

Bilateral renal cryodenervation decreases arterial pressure and improves insulin sensitivity in fructose-fed Sprague-Dawley rats.

Consumption of food high in fructose is prevalent in modern diets. One week of moderately high fructose intake combined with high salt diet has been shown to increase blood pressure and failed to suppress plasma renin activity (PRA). We tested the hypothesis that the hypertension and high PRA are consequences of elevated renal sympathetic nerve activity (RSNA). In protocol 1, we assessed RSNA by telemetry in conscious Sprague-Dawley rats given 20% fructose or 20% glucose in drinking water on a 0.4% NaCl diet (NS) for 1 wk and then transitioned to a 4% NaCl diet (HS). After an additional week, mean arterial pressure (MAP) and RSNA increased significantly in fructose-fed but not glucose-fed HS rats. In protocol 2, fructose (Fruc)- or glucose (Glu)-fed rats on NS or HS diet for 3 wk underwent sham denervation (shamDNX) or bilateral renal denervation using cryoablation (cryoDNX). MAP was higher in Fruc-HS rats compared with Glu-NS, Glu-HS, or Fruc-NS rats and decreased after cryoDNX ( P < 0.01). MAP did not change in Fruc-HS shamDNX rats. Renal norepinephrine content decreased by 85% in cryoDNX ( P < 0.01 vs. shamDNX). PRA significantly decreased after cryoDNX in both Fruc-NS and Fruc-HS rats. Nonfasting blood glucose levels were similar among the four groups. Glucose-to-insulin ratio significantly increased in Fruc-HS cryoDNX rats, consistent with greater insulin sensitivity. Taken together, these studies show that renal sympathoexcitation is, at least in part, responsible for salt-dependent increases in MAP, increased PRA, and decreased insulin sensitivity in rats fed a moderately high fructose diet for as little as 3 wk.

Phosphorylation of rat kidney Na-K pump at Ser938 is required for rapid angiotensin II-dependent stimulation of activity and trafficking in proximal tubule cells.

How angiotensin (ANG) II acutely stimulates the Na-K pump in proximal tubules is only partially understood, limiting insight into how ANG II increases blood pressure. First, we tested whether ANG II increases the number of pumps in plasma membranes of native rat proximal tubules under conditions of rapid activation. We found that exposure to 100 pM ANG II for 2 min, which was previously shown to increase affinity of the Na-K pump for Na and stimulate activity threefold, increased the amount of the Na-K pump in plasma membranes of native tubules by 33%. Second, we tested whether previously observed increases in phosphorylation of the Na-K pump at Ser(938) were part of the stimulatory mechanism. These experiments were carried out in opossum kidney cells, cultured proximal tubules stably coexpressing the ANG type 1 (AT1) receptor, and either wild-type or a S938A mutant of rat kidney Na-K pump under conditions found by others to stimulate activity. We found that 10 min of incubation in 10 pM ANG II stimulated activity of wild-type pumps from 2.3 to 3.5 nmol K · mg protein(-1) · min(-1) and increased the amount of the pump in the plasma membrane by 80% but had no effect on cells expressing the S938A mutant. We conclude that acute stimulation of Na-K pump activity in native rat proximal tubules includes increased trafficking to the plasma membrane and that phosphorylation at Ser(938) is part of the mechanism by which ANG II directly stimulates activity and trafficking of the rat kidney Na-K pump in opossum kidney cells.

Hemodynamic and neural responses to renal denervation of the nerve to the clipped kidney by cryoablation in two-kidney, one-clip hypertensive rats.

Renal artery stenosis is increasing in prevalence. Angioplasty plus stenting has not proven to be better than medical management. There has been a reluctance to use available denervation methodologies in this condition. We studied conscious, chronically instrumented, two-kidney, one-clip (2K-1C) Goldblatt rats, a model of renovascular hypertension, to test the hypothesis that renal denervation by cryoablation (cryo-DNX) of the renal nerve to the clipped kidney decreases mean arterial pressure (MAP), plasma and tissue ANG II, and contralateral renal sympathetic nerve activity (RSNA). Five-week-old male Sprague-Dawley rats underwent sham (ShC) or right renal artery clipping (2K-1C), placement of telemetry transmitters, and pair-feeding with a 0.4% NaCl diet. After 6 wk, rats were randomly assigned to cryo-DNX or sham cryotreatment (sham DNX) of the renal nerve to the clipped kidney. MAP was elevated in 2K-1C and decreased significantly in both ShC cryo-DNX and 2K-1C cryo-DNX. Tissue norepinephrine was ∼85% lower in cryo-DNX kidneys. Plasma ANG II was higher in 2K-1C sham DNX but not in 2K-1C cryo-DNX vs ShC. Renal tissue ANG II in the clipped kidney decreased after cryo-DNX. Baseline integrated RSNA of the unclipped kidney was threefold higher in 2K-1C versus ShC and decreased in 2K-1C cryo-DNX to values similar to ShC. Maximum reflex response of RSNA to baroreceptor unloading in 2K-1C was lower after cryo-DNX. Thus, denervation by cryoablation of the renal nerve to the clipped kidney decreases not only MAP but also plasma and renal tissue ANG II levels and RSNA to the contralateral kidney in conscious, freely moving 2K-1C rats.

Haemodynamic and renal sympathetic responses to V1b vasopressin receptor activation within the paraventricular nucleus.

NEW FINDINGS: What is the central question of this study? Does antagonism of V1b receptors prevent the haemodynamic and renal sympathetic nerve responses that occur with application of exogenous vasopressin into the paraventricular nucleus (PVN) of conscious, chronically instrumented rats? What is the main finding and its importance? Microinjection of vasopressin into the PVN increased mean arterial pressure, heart rate and renal sympathetic nerve activity, all of which were inhibited by pre-injection of the PVN with the V1b antagonist, nelivaptan. The administered vasopressin did not enter the peripheral circulation or increase plasma vasopressin. Ganglionic blockade prevented each of the responses, consistent with mediation by enhanced sympathetic output rather than an increase in circulating vasopressin. Vasopressin (VP) participates in regulation of haemodynamics and volume. Besides more classical actions as a circulating hormone, VP may act via release from axons and dendrites within the CNS. The paraventricular nucleus (PVN) possesses vasopressinergic neurons and a dense complement of VP receptors, including the V1b receptor, which has been implicated in several types of stress responses. We tested the hypothesis that antagonism of V1b receptors will prevent VP-induced increases in mean arterial pressure (MAP), heart rate (HR) and renal sympathetic nerve activity (RSNA). Studies were performed in conscious male Sprague-Dawley rats chronically instrumented with vascular catheters, renal nerve electrodes and a cannula stereotaxically directed into the PVN. Unilateral microinjection of VP into the PVN significantly increased MAP, HR and RSNA, peaking at 10 min. Pre-injection of the PVN with the selective V1b receptor antagonist, nelivaptan, did not alter baseline values but blocked the responses to VP. Ganglionic blockade with chlorisondamine decreased MAP and HR and abolished their increase in response to subsequent PVN application of VP. Injection of VP into the PVN did not alter plasma VP levels. Paraventricular nucleus injection with radiolabelled VP resulted in negligible radiolabelled VP in peripheral blood. These findings support the concept that, in basal conditions, PVN V1b receptor activation (rather than VP release into the periphery) may be implicated in the increases in MAP, HR and RSNA due to increased sympathetic outflow. While the role of V1a and oxytocin receptors cannot be excluded, these data suggest that further studies of the role of V1b receptor activation by endogenous VP during stress to effect neuroexcitation are warranted.

Coagulopathy and spontaneous hemorrhage in a patient with nephrotic syndrome.

Patients with nephrotic syndrome, particularly those with membranous nephropathy tend to be in a hypercoagulable state and often present with thromboembolic phenomena. The association of nephrotic syndrome with a bleeding diathesis however is much less common and the etiologies less well recognized. We report a patient who presented with coagulopathy and recurrent spontaneous hemorrhage in association with nephrotic syndrome. The case highlights key diagnostic and therapeutic challenges and strategies: 1) work up to establish a unifying etiology for both nephrotic syndrome and the bleeding disorder; 2) decision making to obtain a tissue biopsy, select the site of biopsy and understand the relative yields for each site; 3) recognizing the risk and managing peri-procedural bleeding; and 5) developing a treatment strategy with the lowest risk of possible complications. Our patient underwent a kidney biopsy without any complications and a definitive diagnosis of AL amyloidosis was reached. He was treated with anti-plasma cell chemotherapy followed by autologous stem cell transplant with resultant complete hematologic response, improved coagulation parameters, and no further bleeding.

Acute Intake of Fructose Increases Arterial Pressure in Humans: A Meta-Analysis and Systematic Review.

Hypertension is a major cardiac risk factor. Higher blood pressures are becoming more prevalent due to changing dietary habits. Here, we evaluated the impact on blood pressure in human subjects after acutely ingesting fructose using meta-analysis. A total of 89 studies were collected from four different electronic databases from 1 January 2008 to 1 August 2023. Of these studies, 10 were selected that fulfilled all the criteria for this meta-analysis. Heart rate (HR), systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial blood pressure (MAP), and blood glucose level were analyzed using the Cohen's d analysis or standardized mean difference at a confidence interval (CI) of 95%. The SBP, DBP, and MAP showed medium effect size; HR and glucose level displayed small effect size. The standardized mean difference of normal diet groups and fructose diet groups showed a significant increase in SBP (p = 0.04, REM = 2.30), and DBP (p = 0.03, REM = 1.48) with heterogeneity of 57% and 62%, respectively. Acute fructose ingestion contributes to an increase in arterial pressure in humans. The different parameters of arterial pressure in humans correlated with each other. These findings support further rigorous investigation, retrospective of necessity, into the effect of chronic dietary of fructose in humans in order to better understand the impact on long term arterial pressure.

Impact of inhibition of the renin-angiotensin system on early cardiac and renal abnormalities in Sprague Dawley rats fed short-term high fructose plus high salt diet.

Introduction: The combination of a high fructose and high salt diet typical of western diet induces high blood pressure, aortic stiffening, left ventricular (LV) diastolic dysfunction and impaired renal function in rodents. Despite an activated renin-angiotensin system (RAS) in rats fed high fructose and high salt, acute inhibition of the RAS pathway does not improve cardiac and vascular parameters. It may well be that longer term treatment is required to permit remodeling and improve cardiovascular function. Thus, we hypothesized that chronic RAS inhibition fructose+high salt-fed rats to restore blood pressure (BP) to levels similar to glucose plus normal salt-fed controls will improve cardiorenal function and histopathology. Methods: Male and female Sprague Dawley rats monitored by hemodynamic telemetry were fed 0.4% NaCl chow during baseline, then changed to chow containing either 20% glucose+0.4% NaCl (G) or 20% fructose+4% NaCl (F) and treated with vehicle, enalapril (Enal, 4 mg/kg/d) or losartan (Los, 8 mg/kg/d) by osmotic minipump for 25-26 days. Results: BP was elevated in the fructose+high salt groups of both sexes (P < 0.05) and restored to control levels by Enal or Los. Pulse wave velocity (PWV) was lower in female F+Los rats and cardiac output higher in female F+Enal rats. GFR was not changed by diet or treatment. Fructose+high salt groups of both sexes displayed higher albuminuria that was decreased by Enal in male rats. Cardiac fibrosis and mesangial hypercellularity were greater in fructose+high salt-fed rats of both sexes and improved with either Los or Enal. Discussion: Thus, inhibition of the RAS improves early changes in cardiac and renal histopathology in both sexes and albuminuria in male rats fed high fructose and high salt diet. Functional improvements in cardiorenal parameters may require longer treatment.

Paraventricular nucleus control of blood pressure in two-kidney, one-clip rats: effects of exercise training and resting blood pressure.

Exercise-induced changes in γ-aminobutyric acid (GABA) or nitric oxide signaling within the paraventricular nucleus (PVN) have not been studied in renovascular hypertension. We tested whether exercise training decreases mean arterial pressure (MAP) and renal sympathetic nerve activity (RSNA) in two-kidney, one-clip (2K-1C) hypertensive rats due to enhanced nitric oxide or GABA signaling within PVN. Conscious, unrestrained male Sprague-Dawley rats with either sham (Sham) or right renal artery clipping (2K-1C) were assigned to sedentary (SED) or voluntary wheel running (ExT) for 6 or 12 wk. MAP and angiotensin II (ANG II) were elevated in 2K-1C SED rats. The 2K-1C ExT rats displayed lower MAP at 6 wk that did not decline further by 12 wk. Plasma ANG II was lower in 2K-1C ExT rats. Increases in MAP, heart rate, and RSNA to blockade of PVN nitric oxide in 2K-1C SED rats were attenuated compared with either Sham group. Exercise training restored the responses in 2K-1C ExT rats. The increase in MAP in response to bicuculline was inversely correlated with baseline MAP. The rise in MAP was lower in 2K-1C SED vs. either Sham group and was normalized in the 2K-1C ExT rats. Paradoxically, heart rate and RSNA responses were not diminished in 2K-1C SED rats but were significantly lower in the 2K-1C ExT rats. Thus the decrease in arterial pressure in 2K-1C hypertension associated with exercise training is likely due to diminished excitatory inputs to PVN because of lower ANG II and higher nitritergic tone rather than enhanced GABA inhibition of sympathetic output.

Angiotensin II-dependent phosphorylation at Ser11/Ser18 and Ser938 shifts the E2 conformations of rat kidney Na+/K+-ATPase.

Kidney plasma membranes, which contain a single α-1 isoform of Na+/K+-ATPase, simultaneously contain two sub-conformations of E2P, differing in their rate of digoxin release in response to Na+ and ATP. Treating cells with Ang II (angiotensin II) somehow changes the conformation of both, because it differentially inhibits the rate of digoxin release. In the present study we tested whether Ang II regulates release by increasing phosphorylation at Ser11/Ser18 and Ser938. Opossum kidney cells co-expressing the AT1a receptor and either α-1.wild-type, α-1.S11A/S18A or α-1.S938A were treated with or without 10 nM Ang II for 5 min, increasing phosphorylation at the three sites. Na+/K+-ATPase was bound to digoxin-affinity columns in the presence of Na+, ATP and Mg2+. A solution containing 30 mM NaCl and 3 mM ATP eluted ~20% of bound untreated Na+/K+-ATPase (Population #1). Pre-treating cells with Ang II slowed the elution of Population #1 in α-1.wild-type and α-1.S938A, but not α-1.S11A/S18A cells. Another 50% of bound Na+/K+-ATPase (Population #2) was subsequently eluted in two phases by a solution containing 150 mM NaCl and 3 mM ATP. Ang II increased the initial rate and slowed the second phase in α-1.wild-type, but not α-1.S938A, cells. Thus Ang II changes the conformation of two forms of EP2 via differential phosphorylation.

Fructose-induced salt-sensitive blood pressure differentially affects sympathetically mediated aortic stiffness in male and female Sprague-Dawley rats.

Hypertension is the leading risk factor for major adverse cardiovascular events (MACE). Aortic stiffness and sympathoexcitation are robust predictors of MACE. Combined high fructose and sodium intake increases arterial pressure, aortic stiffness, renin, and sympathetic nerve activity in male rats. We hypothesized that activation of the renin angiotensin system (RAS) and/or the sympathetic system mediates aortic stiffness in rats with fructose-induced salt-sensitive blood pressure. Male and female Sprague-Dawley rats ingested 20% fructose or 20% glucose in drinking water with 0.4% NaCl chow for 1 week. Then, fructose-fed rats were switched to 4% NaCl chow (Fru + HS); glucose-fed rats remained on 0.4% NaCl chow (Glu + NS, controls for caloric intake). After 2 weeks, mean arterial pressure (MAP) and aortic pulsed wave velocity (PWV) were evaluated at baseline or after acute intravenous vehicle, clonidine, enalapril, losartan, or hydrochlorothiazide. Baseline global longitudinal strain (GLS) was also assessed. MAP and PWV were greater in male Fru + HS versus Glu + NS male rats (p < 0.05 and p < 0.001, respectively). PWV was similar between the female groups. Despite similarly reduced MAP after clonidine, PWV decreased in Fru + HS versus Glu + NS male rats (p < 0.01). Clonidine induced similar decreases in MAP and PWV in females on either diet. GLS was lower in Fru + HS versus Glu + NS male rats and either of the female groups. Thus, acute sympathoinhibition improved aortic compliance in male rats with fructose salt-sensitive blood pressure. Female rats retained aortic compliance regardless of diet. Acute RAS inhibition exerted no significant effects. Male rats on fructose high salt diet displayed an early deficit in myocardial function. Taken together, these findings suggest that adult female rats are protected from the impact of fructose and high salt diet on blood pressure, aortic stiffness, and early left ventricular dysfunction compared with male rats.

Hypokalemia-Induced Life-Threatening Arrhythmia in a Patient With Congestive Heart Failure.

Ventricular tachyarrhythmias are common in patients with heart failure. It is one of the important preventable causes of death in these patient populations. Hypokalemia is prevalent in patients with heart failure due to various reasons. Hypokalemia can trigger ventricular arrhythmias through different mechanisms. In this case report, we present a middle-aged man with congestive heart failure (CHF) and an automated intracardiac defibrillator (AICD) on multiple diuretic medications (unintended) who presented with acute chest pain. He was found to have severe hypokalemia, hyponatremia, and an acute kidney injury. Interrogation of the AICD revealed multiple episodes of ventricular fibrillation. The patient was managed by holding his diuretic medications, cautious volume repletion, and potassium replacement. Fortunately, the patient showed rapid clinical improvement and his plasma potassium level improved. On discharge, we reconciled the patient's medications to avoid the recurrence of hypokalemia from over-diuresis and arranged a close follow-up outpatient visit with his cardiologist.

Hyperglycinuria: diagnosis in middle age.

Isolated hyperglycinuria is a rare disorder that is associated with osteoporosis and renal calculi. We report findings in a middle-aged, black woman who presented for renal function evaluation with a history of transient hypobicarbonataemia associated with topiramate therapy. She displayed the full triad of high urinary glycine, early-onset osteopenia despite normal reproductive hormones, and renal calculus with high urinary oxalate, phosphate and uric acid. Parathyroid hormone and fibroblast growth factor 23 were both normal. Formal genetic testing did not reveal mutations in SLC6A20, SLC6A18, SLC6A19, SLC36A2, the known genes associated with glycinuria; however, black individuals are poorly represented in the genetic databases. It may well be that otherwise unidentified mutations may be present or that topiramate may result in a lingering proximal tubule defect even after cessation of the drug.

Impact of Dietary Fructose and High Salt Diet: Are Preclinical Studies Relevant to Asian Societies?

Fructose consumption, especially in food additives and sugar-sweetened beverages, has gained increasing attention due to its potential association with obesity and metabolic syndrome. The relationship between fructose and a high-salt diet, leading to hypertension and other deleterious cardiovascular parameters, has also become more evident, especially in preclinical studies. However, these studies have been modeled primarily on Western diets. The purpose of this review is to evaluate the dietary habits of individuals from China, Japan, and Korea, in light of the existing preclinical studies, to assess the potential relevance of existing data to East Asian societies. This review is not intended to be exhaustive, but rather to highlight the similarities and differences that should be considered in future preclinical, clinical, and epidemiologic studies regarding the impact of dietary fructose and salt on blood pressure and cardiovascular health worldwide.

Dietary fructose and high salt in young male Sprague Dawley rats induces salt-sensitive changes in renal function in later life.

Dietary fructose and salt are associated with hypertension and renal disease. Dietary input during critical postnatal periods may impact pathophysiology in maturity. The highest consumption of fructose occurs during adolescence. We hypothesized that a diet high in fructose with or without high salt in young male Sprague Dawley rats will lead to salt-sensitive hypertension, albuminuria, and decreased renal function in maturity. Four groups were studied from age 5 weeks: 20% glucose + 0.4% salt (GCS-GCS) or 20% fructose + 4% salt throughout (FHS-FHS). Two groups received 20% fructose + 0.4% salt or 20% fructose + 4% salt for 3 weeks (Phase I) followed by 20% glucose + 0.4% salt (Phase II). In Phase III (age 13-15 weeks), these two groups were challenged with 20% glucose + 4% salt, (FCS-GHS) and (FHS-GHS), respectively. Each group fed fructose in Phase I exhibited significantly higher MAP than GCS-GCS in Phase III. Net sodium balance, unadjusted, or adjusted for caloric intake and urine flow rate, and cumulative sodium balance were positive in FHS during Phase I and were significantly higher in FCS-GHS, FHS-GHS, and FHS-FHS vs GCS-GCS during Phase III. All three groups fed fructose during Phase I displayed significantly elevated albuminuria. GFR was significantly lower in FHS-FHS vs GCS-GCS at maturity. Qualitative histology showed mesangial expansion and hypercellularity in FHS-FHS rats. Thus, fructose ingestion during a critical period in rats, analogous to human preadolescence and adolescence, results in salt-sensitive hypertension and albuminuria in maturity. Prolonged dietary fructose and salt ingestion lead to a decline in renal function with evidence suggestive of mesangial hypercellularity.

Paraventricular Nucleus V1a Receptor Knockdown Blunts Neurocardiovascular Responses to Acute Stress in Male Rats after Chronic Mild Unpredictable Stress.

Chronic stress and depression impart increased risk for adverse cardiovascular events. Autonomic dysregulation, particularly sympathoexcitation, has long been associated with poor cardiovascular outcomes. Vasopressin (AVP) receptors with the paraventricular nucleus (PVN), known as an integrating locus for hemodynamic and autonomic function, have been implicated in behavior and stress. The present studies were designed to test the hypothesis that knockdown of vasopressin V1aR within the PVN in male Sprague Dawley rats subjected to chronic mild unpredictable stress (CMS) would result in lower resting hemodynamics and renal sympathetic nerve activity (RSNA) and mitigate the responses to acute stressors. Male rats underwent CMS for 4 weeks; controls were housed in standard caging. Twenty days into the paradigm, the PVN was injected with either small interfering RNA (siRNA) directed against V1aR or scrambled RNA (scrRNA). Arterial pressure, heart rate and RSNA were ascertained by telemetry with the animals in their home cages. Pretreatment with siRNA to V1aR prevented the increase in arterial pressure to PVN microinjection with exogenous AVP. Basal mean arterial pressure (MAP) was significantly higher in scrRNA-treated but not in siRNA-treated CMS rats vs control rats. Paradoxically, basal RSNA was approximately two-fold higher in siRNA-treated CMS rats. Acute emotional stress delivered as 15-sec air-jet resulted in greater peak and duration of the MAP and RSNA responses in scrRNA-treated CMS rats vs control; siRNA treatment inhibited the responses. The 15-sec exposure to ammonia to test the nasopharyngeal reflex, whose circuitry does not include the PVN, produced similar increases in arterial pressure, heart rate, and RSNA in controls and both groups of CMS rats. Thus, CMS increases arterial pressure and predisposes to greater hemodynamic and RSNA responses to acute emotional stress. The higher basal RSNA in siRNA-treated rats may be due to functional and/or anatomical neuroplasticity occurring during more protracted inhibition of V1aR PVN signaling. Vasopressinergic signaling via V1aR in PVN modulates the cardiovascular and sympathetic responses to both the chronic and acute stress.

Fructose plus High-Salt Diet in Early Life Results in Salt-Sensitive Cardiovascular Changes in Mature Male Sprague Dawley Rats.

Fructose and salt intake remain high, particularly in adolescents and young adults. The present studies were designed to evaluate the impact of high fructose and/or salt during pre- and early adolescence on salt sensitivity, blood pressure, arterial compliance, and left ventricular (LV) function in maturity. Male 5-week-old Sprague Dawley rats were studied over three 3-week phases (Phases I, II, and III). Two reference groups received either 20% glucose + 0.4% NaCl (GCS-GCS) or 20% fructose + 4% NaCl (FHS-FHS) throughout this study. The two test groups ingested fructose + 0.4% NaCl (FCS) or FHS during Phase I, then GCS in Phase II, and were then challenged with 20% glucose + 4% NaCl (GHS) in Phase III: FCS-GHS and FHS-GHS, respectively. Compared with GCS-GCS, systolic and mean pressures were significantly higher at the end of Phase III in all groups fed fructose during Phase I. Aortic pulse wave velocity (PWV) was elevated at the end of Phase I in FHS-GHS and FHS-FHS (vs. GCS-GCS). At the end of Phase III, PWV and renal resistive index were higher in FHS-GHS and FHS-FHS vs. GCS-GCS. Diastolic, but not systolic, LV function was impaired in the FHS-GHS and FHS-FHS but not FCS-FHS rats. Consumption of 20% fructose by male rats during adolescence results in salt-sensitive hypertension in maturity. When ingested with a high-salt diet during this early plastic phase, dietary fructose also predisposes to vascular stiffening and LV diastolic dysfunction in later life.