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Renal immune cell infiltration and accompanying inflammation activates renal sodium transporters leading to sodium retention and hypertension. Lymphatic vessels traffic interstitial immune cells to the draining lymph nodes and help resolve inflammation. We have previously demonstrated that genetically inducing renal lymphangiogenesis prevents hypertension associated with a reduction in renal immune cell accumulation; however, it is unknown whether augmenting renal lymphatics can treat hypertension. Our hypothesis was that augmenting renal lymphatics after hypertension is established will lower blood pressure during L-NAME-induced hypertension (LHTN). Transgenic mice that overexpress the lymphangiogenic signal VEGF-D only in the kidney upon doxycycline administration (KidVD+ mice) and KidVD- littermates were administered L-NAME (0.5 mg/mL) in their drinking water for four weeks with doxycycline initiated at the second week of L-NAME. Treatment with L-NAME for one week induced LHTN in both KidVD- and KidVD+ mice (SBP: 134±4 and 142±5 mmHg, respectively). However, doxycycline-induced renal lymphangiogenesis significantly decreased blood pressure in KidVD+ mice compared to KidVD- mice after four weeks of L-NAME (SBP: 127±5 vs. 151±6 mmHg; p+ F4/80 - monocytes and a significant increase in 24-hour urinary sodium excretion and fractional excretion of sodium in KidVD+ mice. Urinary volume over 24 hours was also increased in KidVD+ mice (1.7±0.8 vs. 3±0.9 mL/24 hours; p

Aim In nephrotic syndrome, aberrantly filtered plasminogen (plg) is converted to active plasmin by tubular urokinase-type plasminogen activator (uPA) and thought to lead to sodium retention by proteolytic activation of the epithelial sodium channel (ENaC). This concept predicts that uPA is an important factor for sodium retention and that inhibition of uPA might be protective in nephrotic syndrome. Methods Activation of amiloride-sensitive currents by uPA and plg were studied in Xenopus laevis oocytes expressing murine ENaC. In doxorubicin-induced nephrotic mice, uPA was inhibited pharmacologically by amiloride and genetically by the use of uPA-deficient mice (uPA(-/-)). Results Experiments in Xenopus laevis oocytes expressing murine ENaC confirmed proteolytic ENaC activation by a combination of plg and uPA which stimulated amiloride-sensitive currents with concomitant cleavage of the ENaC gamma-subunit at the cell surface. Treatment of nephrotic wild-type mice with amiloride inhibited urinary uPA activity, prevented urinary plasmin formation and sodium retention. In nephrotic mice lacking uPA (uPA(-/-)), urinary plasmin formation from plg was suppressed and urinary uPA activity absent. However, in nephrotic uPA(-/-) mice, sodium retention was not reduced compared to nephrotic uPA(+/+) mice. Amiloride prevented sodium retention in nephrotic uPA(-/-) mice which confirmed the critical role of ENaC in sodium retention. Conclusion uPA is responsible for the conversion of aberrantly filtered plasminogen to plasmin in the tubular lumen in vivo. However, uPA-dependent plasmin generation is not essential for ENaC-mediated sodium retention in experimental nephrotic syndrome.

Primary hyperaldosteronism, or Conn’s syndrome, is a disorder of excessive secretion of aldosterone from the adrenal gland(s). The aldosterone excess results in sodium retention, volume expansion, and hypertension. Complications from long-standing disease include hypokalemia, arrhythmias, heart attack, and stroke.

Edema is a common complication of numerous renal disease. In the recent past several aspects of the pathophysiology of this condition have been elucidated. We herein present a case of nephrotic syndrome in a 30 year-old men. The discussion revolves around the following key questions on fluid accumulation in renal disease: 1. What is edema? What diseases can cause edema? 2. What are the mechanisms of edema in nephrotic syndrome? 2a. The “underfill” theory 2b. The “overfill” theory 2c. Tubulointerstitial inflammation 2d. Vascular permeability 3. What are the mechanisms of edema in nephritic syndrome? 4. How can the volume status be assessed in patients with nephrotic syndrome? 5. What are therapeutic strategies for edema management? 6. What are the factors affecting response to diuretics? 7. How can we overcome the diuretics resistance? 7a. Effective doses of loop diuretics 7b. Combined diuretic therapy 7c. Intravenous administration of diuretics 7d. Albumin infusions 7e. Alternative methods of edema management 8. Conclusion.

Patients with heart failure (HF) now rarely present in cardiogenic shock. Instead, HF has become a chronic systemic disease in which symptoms and disease progression are related to unrestrained neurohumoral stimulation, leading to water and sodium retention [(1)][1]. Because the kidneys are

Angiotensin-converting enzyme (ACE) plays a key role in renal inflammation and sodium retention associated with diabetic nephropathy. Although most effects of ACE have been classically related to angiotensin (Ang) II synthesis, studies highlight an Ang II-independent role of ACE in inflammation. Indeed, ACE has two catalytic domains, the N- and C-domains, that can process a wide diversity of substrates besides Ang I. Here, we study the relative contributions of ACE domains to renal inflammation and sodium retention during diabetic nephropathy. Diabetes was induced with streptozotocin in wild-type (WT) mice and mice lacking either a functional ACE N-domain (NKO) or C-domain (CKO) (n=5-8). After 6 months of diabetes, we evaluated the natriuretic response to volume expansion. For this, mice were injected with 0.9% NaCl equivalent to 10% of their body weight. After 5 hours, diabetic NKO mice excreted 30% more urinary sodium in response to the saline challenge compared to diabetic WT or CKO mice ( P P P P P P P =NS). We next evaluated whether the anti-inflammatory tetrapeptide N-acetyl-seryl-asparyl-lysyl-proline (AcSDKP), an ACE N-domain specific substrate, mediates the protective phenotype of NKO. For this, diabetic mice were treated with the prolyl oligopeptidase inhibitor, S17092 (10 mg/kg, IP), that prevents the synthesis of AcSDKP. In diabetic NKO mice receiving S17092, sodium excretion in response to a saline challenge, ENaC α and γ subunit cleavage, renal inflammation and renal injury were indistinguishable from equally treated diabetic WT mice. In summary, these data indicate that increasing AcSDKP by blocking the ACE N-domain improves sodium handling and ameliorates diabetic kidney disease independently of intrarenal Ang II regulation.

Aim: Hypertension (HTN) is positively correlated with age and sympathetic tone in humans. We hypothesize that sympathetically driven sodium chloride cotransporter (NCC)-mediated sodium retention contributes to age-related HTN. Methods: Three, 8 and 16 month old male SD rats on a normal salt (NS; 0.6% NaCl) diet underwent an acute IV volume expansion (VE; 5% body weight – mechanoreceptor stimulus) or 1M NaCl infusion (20μL/min, 2hr – chemoreceptor stimulus) and mean arterial pressure (MAP), natriuresis (UNaV) and paraventricular nucleus (PVN) neuronal activation (c-Fos expression) were assessed. In separate groups of rats fed a 21 day NS or high salt (HS; 4% NaCl) diet, 1) ex vivo afferent renal nerve (ARN) activity (norepinephrine-evoked substance P release) or 2) in vivo MAP, NCC activity (ΔUNaV to IV hydrochlorothiazide, 2mg/kg) and sympathetic tone were assessed. N=4-6/gp. Results: The natriuretic and PVN sympathoinhibitory parvocellular neuronal responses to VE, but not 1M NaCl infusion, are blunted in aged rats. Aged rats exhibit reduced ARN activity on a NS diet and fail to increase ARN activity on a HS diet. Aged rats develop salt sensitive HTN accompanied by elevated NCC activity and sympathetic tone on a NS diet and impaired suppression of NCC activity and sympathetic tone on a HS diet. Conclusion: Aging is associated with a selective impairment in the mechanosensitive ARN and salt sensitive HTN. We speculate that an age-related decrease in the mechanosensitive ARN sympathoinhibitory reno-renal reflex promotes sympathoexcitation, perhaps via reduced activity of PVN sympathoinhibitory parvocellular neurons, driving NCC-mediated sodium retention and salt sensitive HTN.

Creatine kinase (CK) rapidly regenerates ATP for Na(+)/K(+)‐ATPase driven sodium retention throughout the kidney. Therefore, we assessed whether resting plasma CK is associated with sodium retention after a high sodium diet. Sixty healthy men (29 European and 31 African ancestry) with a mean age of 37.2 years (SE 1.2) were assigned to low sodium intake ( 200 mmol/d). Sodium excretion (mmol/24‐h) after high sodium was 260.4 (28.3) in the high CK tertile versus 415.2 (26.3) mmol/24‐h in the low CK tertile (P

The renal nerves contribute to hypertension through effects in the kidney that enhance sodium retention and renin secretion, and by effects in the central nervous system that increase systemic sympathetic activity. Therefore, targeting the renal nerves provides a logical basis for treating hypertension. Several trials of renal denervation––achieved by applying radiofrequency energy through catheters placed in the renal arteries–– have been completed. Clinical results have been inconsistent, however, partly because of factors related to the ablation technique and partly because these studies have been performed in patients with the inadequately defined clinical condition of “treatment-resistant hypertension.” This statement now explains our conclusion that future studies of renal denervation should be guided by the established randomized, controlled clinical trial designs used for studying antihypertensive drugs and other treatments for hypertension. © 2015 Wiley Periodicals, Inc.

AIM Recent work has demonstrated that activation of the epithelial sodium channel (ENaC) by aberrantly filtered serine proteases causes sodium retention in nephrotic syndrome. The aim of this study was to elucidate a potential role of plasma kallikrein (PKLK) as a candidate serine protease in this context. METHODS We analysed PKLK in the urine of patients with chronic kidney disease (CKD, n = 171) and investigated its ability to activate human ENaC expressed in Xenopus laevis oocytes. Moreover, we studied sodium retention in PKLK-deficient mice (klkb1-/- ) with experimental nephrotic syndrome induced by doxorubicin injection. RESULTS In patients with CKD, we found that PKLK is excreted in the urine up to a concentration of 2 μg mL-1 which was correlated with albuminuria (r = .71) and overhydration as assessed by bioimpedance spectroscopy (r = .44). PKLK increased ENaC-mediated whole-cell currents, which was associated with the appearance of a 67 kDa γ-ENaC cleavage product at the cell surface consistent with proteolytic activation. Mutating a putative prostasin cleavage site in γ-ENaC prevented channel stimulation by PKLK. In a mouse model for nephrotic syndrome, active PKLK was present in nephrotic urine of klkb1+/+ but not of klkb1-/- mice. However, klkb1-/- mice were not protected from ENaC activation and sodium retention compared to nephrotic klkb1+/+ mice. CONCLUSION Plasma kallikrein is detected in the urine of proteinuric patients and mice and activates ENaC in vitro involving the putative prostasin cleavage site. However, PKLK is not essential for volume retention in nephrotic mice.

Congestion is the most important pathophysiological condition in the patients with hospitalization for heart failure (HHF). To manage congestion and improve outcome in the HHF patients, it is essential to understand historical process to reach the present concept of congestion and also its hemodynamic and neurohormonal mechanisms. Congestion consists of both sodium and water retentions. Sodium retention involves not only both renin-angiotensin-aldosterone system and sympathetic nerve system, but also vasopressin system. In contrast, water retention is mainly caused by activation of vasopressin system. Congestion caused by these mechanisms impairs the functions of multiorgans. The crosstalk between the heart and other organs is activated via both neurohormonal activation including vasopressin system and hemodynamic changes in HF. It causes the vicious cycle of congestion and finally it becomes life-threatening. Therefore, congestion including multi-organ congestions should be treated as early as possible with appropriate managements. The fundamental concept of treatment for the HHF patients based on clinical evidences, i.e., “the earlier, the better,” will be able to improve outcome for the HHF patients.

Hypertension (HTN) and high-salt diets are important risk factors for stroke and dementia. DOCA-salt is a recognized model of HTN driven by sodium retention and brain renin-angiotensin system (RAS) activation. However, it is unknown whether essential mechanisms regulating the cerebral circulation are altered in DOCA-salt mice, and, if so, whether these alterations are associated with cognitive impairment. To this end, C57BL/6 mice were implanted with 50mg DOCA pellets SQ and received 0.9% NaCl drinking water for 3 weeks. Cerebral blood flow (CBF) was measured in the somatosensory cortex by laser-Doppler flowmetry through a cranial window. DOCA-salt increased systolic blood pressure (BP; 148±3 vs 112±3 mmHg in controls; p0.05). PVM depletion improved novel object exploration (pgp91 mRNA in cerebral vessels from DOCA mice, which was prevented by PVM depletion (p

Congestion is a major reason for hospitalization in acute heart failure (HF). Therapeutic strategies to manage congestion include diuretics, vasodilators, ultrafiltration, vasopressin antagonists, mineralocorticoid receptor antagonists, and potentially also novel therapies such as gut sequesterants and serelaxin. Uncertainty exists with respect to the appropriate decongestion strategy for an individual patient. In this review, we summarize the benefit and risk profiles for these decongestion strategies and provide guidance on selecting an appropriate approach for different patients. An evidence-based initial approach to congestion management involves high-dose i.v. diuretics with addition of vasodilators for dyspnoea relief if blood pressure allows. To enhance diuresis or overcome diuretic resistance, options include dual nephron blockade with thiazide diuretics or natriuretic doses of mineralocorticoid receptor antagonists. Vasopressin antagonists may improve aquaresis and relieve dyspnoea. If diuretic strategies are unsuccessful, then ultrafiltration may be considered. Ultrafiltration should be used with caution in the setting of worsening renal function. This review is based on discussions among scientists, clinical trialists, and regulatory representatives at the 9th Global Cardio Vascular Clinical Trialists Forum in Paris, France, from 30 November to 1 December 2012.

Background There is ongoing discussion regarding the mechanisms underlying edema formation in nephrotic syndrome (NS). Many studies published in the last decade reported that primary renal sodium retention was a major factor in edema formation. However, many of the factors influencing edema formation in NS remain unclear, including the role of arginine vasopressin (AVP).

Background: Urinary plasmin activates the epithelial Na + channel (ENaC) in vitro and may possibly be a mechanism of sodium retention in nephrotic syndrome (NS). This study used a paired design to test the hypothesis that remission of NS is associated with a decreased content of urinary plasmin and reduced ability of patients' urine to activate ENaC. Methods: Samples were collected during active NS and at stable remission from 20 patients with idiopathic NS, aged 9.1 ± 3.2 years. Plasminogen-plasmin concentration was measured with an enzyme-linked immunosorbent assay. Western immunoblotting for plasminogen-plasmin was performed in paired urine samples. The patch clamp technique was used to test the ability of urine to evoke an inward current on collecting duct cells and human lymphocytes. Results: The urinary plasminogen-plasmin/creatinine ratio was 226 [95 % confidence interval (CI) 130-503] μg/mmol in nephrotic urine versus 9.5 (95 % CI 8-12) μg/mmol at remission (p < 0.001). Western immunoblotting confirmed the presence of active plasmin in urine collected during active NS, while samples collected at remission were negative. Nephrotic urine generated an inward amiloride- and α 2-anti-plasmin- sensitive current, whereas the observed increase in current in urine collected at remission was significantly lower (201 ± 31 vs. 29 ± 10 %; p = 0.005). Conclusions: These findings support the hypothesis that aberrantly filtered plasminogen-plasmin may contribute to ENaC activation and mediate primary renal sodium retention during active childhood NS.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most commonly prescribed medications purchased over the counter to treat acute and chronic pain and inflammation associated with a range of medical conditions.1 It is estimated that NSAIDs are prescribed to about 25% of Canadians for short-term use, but overall use is likely much higher with over-the-counter availability.2 Like any medication, the benefits of NSAIDs should be considered in tandem with the potential adverse effects. Side effects range from the mild and common to the severe and infrequent: dyspepsia, gastric or duodenal ulceration, sodium retention and subsequent hypertension, as well as increased incidence of cardiovascular (CV) adverse events. It was the withdrawal of rofecoxib from the market that brought to light the CV risk of NSAIDs and, in fact, a black-box warning now exists in NSAID product monographs, advising caution when prescribing to patients with ischemic heart disease, cerebrovascular disease and/or congestive heart failure.3 This article focuses on the CV effects associated with NSAID use by reviewing the recent literature on this topic.

Over 60 years ago, Dr. Irvine Page proposed the Mosaic Theory of hypertension, which states that many factors, including genetics, environment, adaptive, neural, mechanical and hormonal perturbations interdigitate to raise blood pressure. In the past two decades, it has become clear that common molecular and cellular events in various organs underlie many features of the Mosaic Theory. Two of these are the production of reactive oxygen species (ROS) and inflammation. These factors increase neuronal firing in specific brain centers, increase sympathetic outflow, alter vascular tone and morphology and promote sodium retention in the kidney. Moreover, factors such as genetics and environment contribute to oxidant generation and inflammation. Other common cellular signals, including calcium signaling and endoplasmic reticulum stress are similarly perturbed in different cells in hypertension and contribute to components of Dr. Page’s theory. Thus, Dr. Page’s Mosaic Theory formed a framework for future studies of molecular and cellular signals in the context of hypertension, and has greatly aided our understanding of this complex disease.