The acute pressure natriuresis response is suppressed by selective ETA receptor blockade

Hypertension is a major risk factor for cardiovascular disease. In a significant minority of people, it develops when salt intake is increased (salt-sensitivity). It is not clear whether this represents impaired vascular function or disruption to the relationship between blood pressure (BP) and renal salt-handling (pressure natriuresis, PN). Endothelin-1 (ET-1) regulates BP via ETA and ETB receptor subtypes. Blockade of ETA receptors reduces BP, but promotes sodium retention by an unknown mechanism. ETB blockade increases both BP and sodium retention. We hypothesised that ETA blockade promotes sodium and water retention by suppressing PN. We also investigated whether suppression of PN might reflect off-target ETB blockade. Acute PN was induced by sequential arterial ligation in male Sprague Dawley rats. Intravenous atrasentan (ETA antagonist, 5mg/kg) halved the normal increase in medullary perfusion and reduced sodium and water excretion by >60%. This was not due to off-target ETB blockade because intravenous A-192621 (ETB antagonist, 10mg/kg) increased natriuresis by 50% without modifying medullary perfusion. In a separate experiment in salt-loaded rats monitored by radiotelemetry, oral atrasentan reduced systolic and diastolic BP by ~10mmHg, but additional oral A-192621 reversed these effects. Endogenous ETA stimulation has natriuretic effects mediated by renal vascular dilation while endogenous ETB stimulation in the kidney has antinatriuretic effects via renal tubular mechanisms. Pharmacological manipulation of vascular function with ET antagonists modifies the BP set-point, but even highly selective ETA antagonists attenuate PN, which may be associated with salt and water retention.

Neural basis for regulation of vasopressin secretion by anticipated disturbances in osmolality

Water balance, tracked by extracellular osmolality, is regulated by feedback and feedforward mechanisms. Feedback regulation is reactive, occurring as deviations in osmolality are detected. Feedforward or presystemic regulation is proactive, occurring when disturbances in osmolality are anticipated. Vasopressin (AVP) is a key hormone regulating water balance and is released during hyperosmolality to limit renal water excretion. AVP neurons are under feedback and feedforward regulation. Not only do they respond to disturbances in blood osmolality, but they are also rapidly suppressed and stimulated, respectively, by drinking and eating, which will ultimately decrease and increase osmolality. Here, we demonstrate that AVP neuron activity is regulated by multiple anatomically- and functionally-distinct neural circuits. Notably, presystemic regulation during drinking and eating are mediated by non-overlapping circuits that involve the lamina terminalis and hypothalamic arcuate nucleus, respectively. These findings reveal neural mechanisms that support differential regulation of AVP release by diverse behavioral and physiological stimuli.

Abstract 07: Collecting Duct (Pro) Renin Receptor(PRR) Promotes Kidney Fibrosis Via Macrophage Alternative Activation Mediated By Soluble PRR (sPRR)-Dependent Activation Of Yap/Taz Axis

Renal collecting duct (CD), an important site for fine-tuning urinary Na + and water excretion, is not traditionally thought to play a role in pathogenesis of chronic kidney disease. In the present study, we examined a profibrotic role of CD PRR in a mouse model of unilateral ureteral obstruction (UUO) and further defined the underlying mechanism involving soluble PRR (sPRR)-dependent activation of alternative macrophages activation. We subjected mice with CD-specific deletion of PRR (CD PRR KO) and their floxed controls to UUO or sham surgery. After 7 days of UUO, CD PRR KO decreased the fibronectin (28.6±6.8%) and α-SMA (39.2±7.8%) protein expression in obstructed kidneys. The Masson’s trichrome staining data also showed that CD PRR KO significantly attenuated UUO-induced collagen deposition and histological damage in the kidney. In parallel, CD PRR KO reduced TGF-β1 (56.7±3.2%) and TGF-β2 (53±1.2%) mRNA expression in obstructed kidneys. Moreover, in macrophages sorted from obstructed kidneys of CD PRR KO mice showed a significantly reduced of M2 macrophage markers such as mannose receptor ( MR ) (58.7±2.1%), arginase-1 ( Arg-1 ) (50±1.5%), chitinase-like lectins ( YM-1 ) (59.3±1.9%), inflammatory zone-1 ( Fizz1 ) (39.1±4.1%) mRNA expression and Yes-associated protein ( Yap ) (77±6.8%)/ transcriptional coactivator with PDZ-binding motif ( Taz ) (54.5±1.8%) mRNA expression compared with macrophages sorted from obstructed kidneys of floxed mice. Meanwhile, plasma sPRR was elevated in floxed mice by UUO and this elevation was blunted by CD PRR KO (23.7±0.4%). Administration of site-1 protease (S1P) inhibitor PF-429242 to C57BL/6 mice with UUO almost completely recapitulated the antifibrotic action as well as the inhibitory effect on M2 activation of CD PRR KO. In bone marrow-derived macrophages, sPRR-His treatment promoted macrophage M2 polarization, fibrosis and Yap/Taz expression. Overall, these results suggest that activation of CD PRR releases sPRR that activates M2 polarization via Yap/Taz axis, leading to renal fibrosis during UUO.

Renal, Cardiac, and Autonomic Effects of Catheter-Based Renal Denervation in Ovine Heart Failure

A growing number of clinical studies suggest that in heart failure renal denervation (RDN) has beneficial effects on the autonomic control of the heart. There is also experimental evidence that surgical RDN improves sodium handling and clearance in heart failure. The aim of this study was to determine the effects of catheter-based RDN on the sympathetic and parasympathetic control of the heart, and salt and water handling capacity of the kidneys, in sheep with established heart failure. A randomized, controlled study was conducted in 10 sheep with heart failure (ejection fraction<40%) induced by rapid ventricular pacing. Sheep underwent either bilateral RDN using the Symplicity denervation system or sham denervation and were studied 1 and 6 weeks after RDN. In established ovine heart failure, at 6 weeks after catheter-based RDN, heart rate significantly decreased, estimates of resting and maximal parasympathetic control of heart rate increased, and cardiac sympathetic nerve activity decreased. Compared with sham denervation, there was an increase in the resting sodium and water excretion 6 weeks after catheter-RDN and an improved ability of the kidneys to excrete a nonhypertensive saline load. After catheter-based RDN, renal norepinephrine levels were reduced by 70% compared with sham denervation. In established heart failure, RDN induced a beneficial shift in both arms of the autonomic nervous control of the heart and improved the ability of the kidneys to excrete sodium and water. Thus, effective catheter-based RDN may be beneficial to both the heart and kidneys in heart failure.

Immune Mechanisms of Dietary Salt-Induced Hypertension and Kidney Disease: Harry Goldblatt Award for Early Career Investigators 2020

Salt sensitivity of blood pressure is an independent risk factor for cardiovascular mortality not only in hypertensive but also in normotensive adults. The diagnosis of salt sensitivity of blood pressure is not feasible in the clinic due to lack of a simple diagnostic test, making it difficult to investigate therapeutic strategies. Most research efforts to understand the mechanisms of salt sensitivity of blood pressure have focused on renal regulation of sodium. However, salt retention or plasma volume expansion is not different between salt-sensitive and salt-resistant individuals. In addition, over 70% of extracellular fluid is interstitial and, therefore, not directly controlled by renal salt and water excretion. We discuss in this review how the seminal work by Harry Goldblatt paved the way for our attempts at understanding the mechanisms that underlie immune activation by salt in hypertension. We describe our findings that sodium, entering antigen-presenting cells via an epithelial sodium channel, triggers a PKC (protein kinase C)- and SGK1 (serum/glucocorticoid kinase 1)-stimulated activation of nicotinamide adenine dinucleotide phosphate oxidase, which, in turn, enhances lipid oxidation with generation of highly reactive isolevuglandins. Isolevuglandins adduct to proteins, with the potential to generate degraded peptide neoantigens. Activated antigen-presenting cells increase production of the TH17 polarizing cytokines, IL (interleukin)-6, IL-1β, and IL-23, which leads to differentiation and proliferation of IL-17A producing T cells. Our laboratory and others have shown that this cytokine contributes to hypertension. We also discuss where this sodium activation of antigen-presenting cells may occur in vivo and describe the multiple experiments, with pharmacological antagonists and knockout mice that we used to unravel this sequence of events in rodents. Finally, we describe experiments in mononuclear cells obtained from normotensive or hypertensive volunteers, which confirm that analogous processes of salt-induced immunity take place in humans.

Cucumber and honey soaking reduces hypertension in the elderly

Hypertension is a condition of increasing a person's blood pressure beyond normal limits, causing increased morbidity and mortality. Hypertension can be reduced by consuming cucumber which contains potassium which inhibits the release of renin so that there is an increase in sodium and water excretion. In addition, it can also be reduced by consuming honey which can prevent the formation of plaque attached to the walls of blood vessels so that it can eliminate bad cholesterol for the body. This study aimed to determine the effect of giving cucumber and honey water immersion on Elderly Hypertension. This study used a Quasy Experimental design with a Pretest and Posttest with Control Group design. Sampling using a simple random sampling technique. The sample in this study amounted to 30 elderly people using the paired sample t-test statistical test. The results showed that the average blood pressure of the intervention group before being given the cucumber and honey water immersion was 153.6/84 mmHg and after it was 148.3/82.1 mmHg. The average blood pressure of the control group before being given the cucumber and honey water immersion was 158.5/80.2 mmHg and after it was 163.5/80.2 mmHg with p = 0.000. In the results of the independent sample test the intervention group before being given therapy, namely Sig. (2-tailed) = 0.027, the control group before treatment was Sig. (2-tailed) = 0.045. While the test results of the intervention group after being given therapy are Sig. (2-tailed) = 0.124, the control group after being given therapy is Sig. (2-tailed) = 0.139. There is an effect of giving cucumber and honey water immersion therapy on changes in blood pressure in the elderly with hypertension. But there is no difference in the average blood pressure of the Hypertensive Elderly. It is expected that the elderly with hypertension can make cucumber and honey water immersion as an alternative therapy to reduce hypertension

AT II Receptor Blockade and Renal Denervation: Different Interventions with Comparable Renal Effects?

<b><i>Background:</i></b> Angiotensin II (Ang II) and the renal sympathetic nervous system exert a strong influence on renal sodium and water excretion. We tested the hypothesis that already low doses of an Ang II inhibitor (candesartan) will result in similar effects on tubular sodium and water reabsorption in congestive heart failure (CHF) as seen after renal denervation (DNX). <b><i>Methods:</i></b> Measurement of arterial blood pressure, heart rate (HR), renal sympathetic nerve activity (RSNA), glomerular filtration rate (GFR), renal plasma flow (RPF), urine volume, and urinary sodium. To assess neural control of volume homeostasis, 21 days after the induction of CHF via myocardial infarction rats underwent volume expansion (0.9% NaCL; 10% body weight) to decrease RSNA. CHF rat and controls with or without DNX or pretreated with the Ang II type-1 receptor antagonist candesartan (0.5 ug i.v.) were studied. <b><i>Results:</i></b> CHF rats excreted only 68 + 10.2% of the volume load (10% body weight) in 90 min. CHF rats pretreated with candesartan or after DNX excreted from 92 to 103% like controls. Decreases of RSNA induced by volume expansion were impaired in CHF rats but unaffected by candesartan pointing to an intrarenal drug effect. GFR and RPF were not significantly different in controls or CHF. <b><i>Conclusion:</i></b> The prominent function of increased RSNA – retaining salt and water – could no longer be observed after renal Ang II receptor blockade in CHF rats.

The kidney of the Nodularia freshwater mussel has a larger filtration-size and counter-current system with improved water excretion compared with the seawater mussel Mytilus

Histological studies and magnetic resonance imaging were employed to analyze the kidney structure and function of the freshwater mussel, Nodularia douglasiae. The Nodularia kidney consists of proximal, intermediate and distal tubules. The epithelia of the renal tubules were composed of a single layer of cuboidal cells. The proximal and distal tubules run in opposite directions underneath the pericardial cavity. Molecular weight cut-off (MWCO) values for the kidney filtration were detected by MR tracer injections: gadolinium-diethylenetriamine pentaacetic acid (GdDTPA) at 0.55 kDa, an oligomer-based contrast agent (CH3-DTPA-Gd) at 2.2kDa, as well as Gd-DTPA-polylysine at 10, 22, and 110 kDa. The T1w-MRI intensity and T1 relaxation rate (R1) of the pericardial cavity and renal tubules increased with tracers smaller than 10 kDa. The other tracers showed only minimal or no increase. Thus, we concluded that the MWCO of the kidney is 22 kDa, 50 times larger than that for the Mytilus living in seawater. Since the R1 values of the renal tubules were similar to those of the pericardial cavity, the kidney did not concentrate filtrated tracers. The slow decay of the MR tracers from the renal tubules indicated a low filtration rate, suggesting that the counter-current system reabsorbs useful solutes without reabsorption of water. The higher MWCO may be beneficial to maintain the tubular oncotic pressure and allow excretion of excess water. In conclusion, a main renal function of the freshwater mussel is the excretion of water, opposite to that of the seawater mussel and vertebrates, which preserve water.

Unmasking of Neurosarcoidosis

Introduction: Central diabetes insipidus is a rare complication of neurosarcoidosis. In patients with concomitant adrenal insufficiency (AI), the symptoms of Diabetes Insipidus (DI) can be masked. Case: A 55-year-old female with past medical history of sarcoidosis presented to the hospital with hematemesis, nausea and dizziness. She has a past medical history of cardiac sarcoidosis that was revealed on a PET scan done before 10 years for which she was being treated with methotrexate and prednisone. She was off prednisone for a year prior to hospitalization. She underwent an upper endoscopy that showed diffusely erythematous gastric mucosa in the antrum. She was also hypotensive on admission, and she received packed red blood transfusions after which her sodium increased from 145mmol/L to 165mmol/L (Normal: 135-145mmol/L) in 48 hours. Further workup revealed persistent hypernatremia and urine osmolality was 75mOsm/kg H2O. (Normal: 50-1200mOsm/kg H2O). She was also hypoglycemic and hypotensive requiring multiple fluid boluses throughout her hospitalization. This prompted us to perform a random cortisol that came back at 2.1ug/dl (Normal: 3-23ug/dl) and 1.8ug/dl on two occasions. Cortisol Stimulation test was subsequently ordered, but was done only at 30 minutes, and Cortisol increased from 1.8ug/dl to 6.3ug/dl. Free thyroxine was 0.5 ng/dl (Normal: 0.9-1.8 ng/dl) and her TSH was 7.58uIU/ml (Normal: 0.55-4.78uIU/ml). MRI of the brain revealed extensive areas of extra-axial supra-sellar/infundibular nodular homogeneous intense enhancement that is most consistent with neuro-sarcoid. She was started on prednisone 40 mg daily, Desmopressin 0.05 mg twice daily, and levothyroxine as well. Her sodium level normalized and was 137mmol/L at discharge. She followed up later with outpatient Endocrinology and reported around 90lbs weight gain and no more episodes of nausea or vomiting or epistaxis or lightheadedness. Conclusion: The involvement of the hypothalamic-pituitary axis in sarcoidosis is extremely rare and attributes to &lt; 1% of patients with a sellar mass. Small case series have shown that hypogonadism is the most common endocrine abnormality followed by DI. Our patient had a long-standing history of sarcoidosis with her pituitary dysfunction unmasked only on admission for other causes. She did not manifest any symptoms of DI or AI. There have been case reports where the symptoms of DI are masked due to underlying glucocorticoid deficiency. There have been theories that glucocorticoid deficiency impairs renal water excretion by both ADH (Anti-diuretic hormone) dependent and ADH independent pathways. Another notable feature in our case is that our patient presented with primary hypothyroidism. In fact, sarcoidosis has been commonly implicated in auto-immune polyglandular syndromes type 3, which can present with auto-immune thyroiditis more so in females.

Urea Use for SIADH: A Case Report and Review of the Literature

Introduction: Hyponatremia is the most frequent electrolyte abnormality among hospitalized patients associated with increased morbidity and mortality. There is a demanding need for affordable and well-tolerated therapies, and urea is a compelling alternative for the syndrome of inappropriate diuretic hormone (SIADH). Urea increases renal water excretion due to osmotic diuresis and reduce urinary sodium leading to an increase in serum sodium. This case illustrates the effect and safe use of urea in a hospitalized patient with SIADH. Clinical Case: An 80-year-old male with history of recurrent anterior chest wall chondrosarcoma despite 3 chest wall resections presented to the hospital for a 4th anterior chest wall resection with reconstruction. Physical examination was notable for euvolemia with no neurologic deficits. Pre-operative labs were significant for a plasma sodium (PNa) 118 mmol/L, potassium 4 mmol/L, BUN 9 mg/dL, Cr 0.72 mg/dL, TSH 2.9 mIU/L, cortisol 21.3 mcg/dL, serum osmolality 267 mOsm/kg, urine osmolality 423 mOsm/kg, and urine sodium 115 mmol/L. Underlying SIADH was initially treated with water restriction of 800 mL/24 h. Previously, he was given a trial of salt tabs, which he did not tolerate due to nausea and emesis. Due to profound hyponatremia, he was started on 2% hypertonic saline. Once PNa levels reached 130 mmol/L, 2% saline was discontinued. Repeated PNa showed a decrease to 128mmol/L. Tolvaptan was not initiated due to lack of insurance coverage and hepatotoxicity, and demeclocycline was not considered due to his known allergy. He was ultimately started on urea powder at 15 g/day and tittered to 30 g/day. In one week PNa improved to 135 mmol/L and remained stable until discharge. Clinical Lessons: The cornerstone of therapy for SIADH relies on reducing free water intake but this is not always feasible or sufficient. Winzer et al. [1] showed that fluid restriction is effective in only 59% of the patient with SIADH. As a result, pharmacology therapy is often needed. European guidelines, as compared to American guidelines, recommend the use of urea instead of vaptans therapy as second-line treatment. The above is based on different studies [2] that have shown that urea has similar efficacy, is more cost-effective, and safer since it does not cause liver toxicity like vaptans. Given this response, it appears that urea should be considered as a second-line therapy to fluid restriction given its tolerability and cost-effectiveness when compared to its alternatives. References: 1. Winzeler B, Lengsfeld S, Nigro N, Suter-Widmer I, et al. Predictors of nonresponse to fluid restriction in hyponatremia due to the syndrome of inappropriate antidiuresis. J Intern Med 280: 609–617, 20162. Soupart A, Coffernils M, Couturier B, Gankam-Kengne F, et al. Efficacy and tolerance of urea compared with vaptans for long-term treatment of patients with SIADH. Clin J Am Soc Nephrol 7: 742–747