Renal Sodium Excretion Research Articles

The hypoxia-inducible factor prolyl hydroxylase inhibitor FG4592 promotes natriuresis through upregulation of COX2 in the renal medulla.

The renal medulla is a key site for the regulation of renal sodium excretion. However, the molecular mechanism remains unclear. Cyclooxygenase 2 (COX2) is specifically expressed in the renal medulla and contributes to the maintenance of the electrolyte/water balance in the body. Hypoxia-inducible factors (HIFs) have also been found to be expressed in the renal medulla, probably owing to the hypoxic conditions in the renal medulla. This study was designed to test the effects of HIF activation on renal sodium handling and renal medullary COX2 expression. Our data showed that HIF activation by the prolyl hydroxylase inhibitor (PHI) FG4592 enhanced natriuresis in mice challenged with a high-salt diet. In addition, FG4592 upregulated the expression of COX2 in the renal medulla. An in vitro study further supported the finding that HIF can induce the expression of COX2 and that this induction is mediated through direct binding to the promoter region of the Cox2 gene, facilitating its transcription. In addition, the COX2 inhibitor celecoxib diminished the natriuretic effect of FG4592. Together, these results suggest that HIF activation promotes sodium excretion through upregulation of COX2 in the renal medulla and therefore maintains sodium homeostasis in the body.

Acute Increase of Renal Perfusion Pressure Causes Rapid Activation of mTORC1 (Mechanistic Target Of Rapamycin Complex 1) and Leukocyte Infiltration.

The present study in Sprague-Dawley rats determined the effects of a rapid rise of renal perfusion pressure (RPP) upon the activation of mTOR (mechanistic target of rapamycin), and the effects upon the infiltration of CD68-positive macrophages/monocytes and CD3-positive T lymphocytes into the kidneys. RPP was elevated by 40 mm Hg for 30 minutes in male Sprague-Dawley rats while measuring renal blood flow and urine flow rate. Sham rats were studied in the same way, but RPP was not changed. Since initial studies found that the acute increase of RPP resulted in activation of mTORC1 (phosphorylation of S6S235/236), the effects of inhibition of mTORC1 with rapamycin pretreatment were then determined. It was found that a 30-minute increase of RPP (≈40 mm Hg) resulted in an 8-fold increase of renal sodium excretion which was blunted by rapamycin treatment. Renal blood flow was not affected by the elevation of RPP. Activation of mTORC1 was observed. Significant increases in CD68-positive macrophages were found in both the cortex (intraglomerular and periglomerular regions) and in the outer medullary interstitial regions of the kidney and prevented by rapamycin treatment. Increases in CD3-positive T lymphocytes were observed exclusively in the periglomerular regions and prevented by rapamycin treatment. Upregulation of several proinflammatory markers was observed. We conclude that elevation of RPP rapidly activates mTORC1 resulting in infiltration of immune cells into the kidney.

Science, Medicine, and the Anesthesiologist

Science, Medicine, and the Anesthesiologist

Oral and intravenous hydration in the treatment of orthostatic hypotension and postural tachycardia syndrome.

Hydration with water and salt is the mainstay of treatment for autonomic nervous system disorders that impair orthostatic tolerance. The goal is to expand intravascular volume to compensate for the downward displacement of blood volume that occurs when standing and thereby sustain cerebral perfusion and restore quality of life. Despite strong consensus recommendations for salt supplementation as standard treatment of these disorders, published evidence of benefit is relatively weak, and no randomized clinical trials have occurred. This review summarizes the physiological rationale for hydration and evaluates the literature on oral and intravenous hydration in the treatment of neurogenic orthostatic hypotension, postural tachycardia syndrome, and recurrent vasovagal syncope. We conclude that oral salt replacement is indicated for treatment of neurogenic orthostatic hypotension because these patients have excessive renal sodium excretion, and for treatment of chronic orthostatic intolerance because these patients are often hypovolemic. As not all patients are able to tolerate sufficient oral hydration, there is also a role for intravenous volume-loading in severe cases of postural tachycardia syndrome. We offer guidance, based on review of the literature and the clinical judgment of a cardiologist and neurologist with experience treating autonomic disorders, regarding the option of ongoing intravenous hydration for treatment of severe, refractory cases of postural tachycardia syndrome.

Smanjenje unosa soli kao prvi korak u prevenciji hipertenzije

People consumed salt exclusively through food millions of years ago, which amounted to less than 0.5 g/day. Recent researches indicate that the average daily consumption of salt is more than 10 g/day. The general conclusion of studies investigating the relationship between dietary salt intake and blood pressure led to recommendations on reducing salt intake and limiting total intake to 5 g of salt per day by the World Health Organization and the European Safety Agency of Food. Increased salt intake causes suppression of the Renin-Angiotensin-Aldosterone system by reducing sodium renal excretion. Also, an increase in salt intake leads to an increase in the concentration of sodium in the blood, which causes high secretion of vasopressin and causes high blood pressure. Namely, bread is a basic food and is high in salt, but the salt parameter is not mandatory in accordance with the regulations. Today, almost every EU country has different strategies that include recommending salt reduction through food reformulation to reduce the salt content of food, including bread and bakery products. Achieving and maintaining the reduction of the population's salt intake will soon give a great benefit in terms of the prevention of cardiovascular events as the first cause of death globally, then great savings for the health system and an individual.

The Effect of Swimming Training on Adrenomedullin mRNA Levels in the Aorta, Kidney, and Adrenal Gland of L‐NAME‐induced Hypertensive Rats

Adrenomedullin, which is produced by the vascular endothelial and smooth muscle cells and cardiomyocytes, is considered to be a local factor controlling vascular tone, cardiac contractility, and renal sodium excretion. Hypertension is the most common cause of cardiovascular disorders and diseases. Exercise has beneficial effects on hypertension, but pathophysiological factors involved in exercise‐mediated amelioration of hypertension are yet to be elucidated. We hypothesized that adrenomedullin produced through exercise could play an essential role in the protection from hypertension. For this study rats were subjected to swimming training for six weeks (1‐h per day and five times each week). Meanwhile, hypertension was induced by the oral administration of L‐NAME (60 mg/kg). Here, we show that L‐NAME administration per se leads to a significant increase in mean arterial blood pressure. Notably, the 6‐week swimming exercise causes a protective effect from the development of hypertension. In addition, the rats rescued from hypertension have high mRNA levels of renal adrenomedullin while they have low levels of adrenomedullin mRNA in the aorta. The obtained data indicate that a 6‐week exercise intervention rescues rats from high blood pressure by leading to changes in adrenomedullin levels in the aorta and kidney. The increased expression of adrenomedullin in the aorta might have been a result that compensates for the hypertensive effect of L‐NAME. On the other hand, exercise probably exerts its protective effects on hypertension by increasing adrenomedullin in the kidney. A more extended exercise period may give more apparent results regarding the level of adrenomedullin in different organs.

Blood pressure regulation in autonomic failure by dietary sodium, blood volume and posture

In normal subjects natriuresis is tightly coupled to dietary salt ingestion to maintain sodium balance. Likewise, blood pressure remains unchanged over a wide range of salt intake because of pressure natriuresis, whereby an increase in blood pressure stimulates renal sodium excretion to restore homeostasis. These sodium handling mechanisms are impaired in autonomic failure. When exposed to salt restriction, autonomic failure patients are unable to reduce renal sodium excretion, and their orthostatic hypotension worsens. It follows that increased dietary salt would improve orthostatic tolerance. Indeed, most clinical practice guidelines emphasize a high salt intake (6-10g/day) in the treatment of neurogenic orthostatic hypotension. This approach has been shown to improve other conditions such as syncope and postural tachycardia syndrome, but surprisingly there is no empirical evidence to support this recommendation in orthostatic hypotension. Even though there is expert opinion consensus in its favor, it would be reassuring if at least mechanistic proof of concept studies were available. Fludrocortisone is often added to a high salt diet to improve sodium retention and increase plasma volume, but these effects are transient. Fludrocortisone is contraindicated in patients with heart failure and should be used with caution, if at all, if supine hypertension is present. In patients with supine hypertension posture is an important determinant of sodium balance; blood pressure substantially increases while supine, triggering pressure natriuresis and extensive sodium loss. Thus, avoiding the supine posture may be as important as increasing dietary salt in the management of orthostatic hypotension.

Abstract 10795: Adam10 Gene Deficiency Impairs Kidney Function via Suppressing Klotho Shedding

A Disintegrin and Metalloproteinase 10 (ADAM10) is a member of the ADAM family of cell membrane-anchored proteins which processes and influences the functions of its substrates by in-/activating them or by liberating biologically active fragments. ADAM10 is primarily expressed in kidney epithelial cells. Thus, the objective of this study is to investigate whether ADAM10 is involved in the regulation and maintenance of normal kidney function. Tamoxifen-inducible kidney-specific cre (Ksp) and ADAM170-floxed mice were cross-bred for generating Ksp/ADAM10-floxed mice. Injection of tamoxifen initiated deletion of the ADAM10 gene and led to a significant reduction in ADAM10 protein expression in renal distal and proximal tubule cells. Notably, knockout of the ADAM10 gene largely decreased soluble Klotho levels in urine, indicating that ADAM10 is a critical enzyme in shedding Klotho. We found that renal sodium excretion was decreased in kidney-specific ADAM1 0 knockout mice (ADAM10 -/-), suggesting that ADMA10 deficiency results in an increase in Na reabsorption or Na retention. Urinary potassium output tended to increase in ADAM10 -/- mice although it did not reach a significant level. It is interesting that ADAM10 gene deficiency compromises renal tubular function leading to Na retention. Glomerular filtration rate (GFR) was dramatically decreased in ADAM10 -/- mice, indicating that ADAM10 deficiency impairs glomerular function. Interestingly, treatment with recombinant Klotho improved renal glomerular function. Therefore, ADAM10 gene knockout impairs kidney function likely via suppressing Klotho shedding.

Knockout of Macula Densa Neuronal Nitric Oxide Synthase Increases Blood Pressure in db/db Mice.

[Figure: see text].

Bilateral renal denervation prevents the development of hypertension during diet-induced obesity in male rats.

What is the central question of this study? What is the role of the renal nerves in the development of obesity, hyperlipidaemia and hypertension during the long-term feeding of a moderately high-fat diet in male obesity-prone rats? What is the main finding and its importance? The renal nerves play a prominent mediatory role, without influencing the establishment of visceral adiposity and atherogenic hyperlipidaemia, in the induction and progression of pressure natriuresis impairment and hypertension during the developmental period of diet-induced obesity. Feeding a moderately high-fat (MHF) diet in male Sprague-Dawley rats induces obesity, pressure natriuresis impairment and hypertension. This study investigated the role of the renal nerves in the impaired pressure natriuresis and hypertension caused by feeding a MHF diet. After collecting baseline data on day 0, 12 rats remained on a low-fat diet (LF group) while the others were switched onto a MHF diet and diverged into obesity-resistant (OR) or obesity-prone (OP). After 4weeks, half of the OR and OP rats underwent bilateral renal denervation (BRD) to generate four groups: OR, OR/BRD, OP and OP/BRD (n=12). During 10weeks, body weight, obesity index, systolic pressure and renal excretory function were measured regularly. After 10weeks, renal excretory responses to acute salt loading and renal autoregulation were evaluated. The OP and OP/BRD groups had greater increases of body weight and obesity index during the dietary period compared to the other groups, and by week 10 their body weight (425.1±7.2 and 411.9±5.1g) became considerably larger than that of the LF group (358.5±6.2g). Renal sodium excretion was reduced by ∼20% at week 4 in the OP and OP/BRD groups, while only the OP group had lower sodium excretion at weeks 6-8 and higher systolic pressure over weeks 5-10 than the other groups and its week 10 systolic pressure reached 138.1±6.7 versus 123.6±2.7mmHg of the LF group. The OP group showed delayed renal excretory responses to salt loading with rightward and downward shifts in renal autoregulatory curves. Therefore, the renal nerves exert a main mediatory role in the development of pressure natriuresis impairment and hypertension as obesity is established due to the long-term consumption of the MHF diet in male OP rats.

Abstract 06: Mechanisms And Consequences Of Casein Kinase II And Ankyrin 3 Regulation Of The Epithelial Sodium Channel

Activity of the Epithelial Na+ Channel (ENaC) in the distal nephron fine-tunes renal sodium excretion. Appropriate sodium excretion is a key factor in the regulation of blood pressure. Consequently, abnormalities in ENaC function can cause hypertension. Casein Kinase II (CKII) phosphorylates ENaC. The CKII phosphorylation site in ENaC resides within a canonical “anchor” ankyrin binding motif. CKII-dependent phosphorylation of ENaC is necessary and sufficient to increase channel activity and is thought to influence channel trafficking in a manner that increases activity. We test here the hypothesis that phosphorylation of ENaC by CKII within an anchor motif is necessary for ankyrin-3 (Ank-3) regulation of the channel, which is required for normal channel locale and function, and the proper regulation of renal sodium excretion. This was addressed using a fluorescence imaging strategy combining total internal reflection fluorescence (TIRF) microscopy with fluorescence recovery after photobleaching (FRAP) to quantify ENaC expression in the plasma membrane in living cells; and electrophysiology to quantify ENaC activity in split-open collecting ducts from principal cell-specific Ank-3 knockout mice. Sodium excretion studies also were performed in parallel in this knockout mouse. In addition, we substituted a key serine residue in the consensus CKII site in β-ENaC with alanine to abrogate phosphorylation and disrupt the anchor motif. Findings show that disrupting CKII signaling decreases ENaC activity by decreasing expression in the plasma membrane. In the principal cell-specific Ank-3 KO mouse, ENaC activity and sodium excretion were significantly decreased and increased, respectively. These results are consistent with CKII phosphorylation of ENaC functioning as a “switch” that favors Ank-3 binding to increase channel activity.

Abstract P198: Biphasic And Sex-dependent Roles Of The Prorenin Receptor In The Rostral Ventrolateral Nucleus In Mice Subjected To Deoxycorticosterone Acetate-salt Hypertension

The brain renin angiotensin system (RAS) regulates blood pressure (BP) and autonomic function. However, it remains unclear how and where angiotensin II (Ang II) is generated in conditions eliciting brain RAS overactivation including deoxycorticosterone acetate (DOCA)-salt hypertension (HT). In several tissues, the activation of prorenin requires its binding to the prorenin receptor (PRR). New evidence from this study indicates that prorenin and PRR are co-expressed in the proximity to the rostral ventrolateral nucleus (RVL), an anatomical brain region that controls sympathetic nerve activity. Therefore, we hypothesized that selective ablation of PRR targeting the RVL attenuates BP increase due to DOCA-salt. PRR ablation was targeted to the RVL by stereotactic microinjections of adeno-associated virus (AAV) expressing Cre recombinase-mCherry in PRR-flox mice (PRR RVL-KO ). AAV mCherry was used as control virus (WT). A pressor response to L-glutamate in the injection site served as confirmatory stereotactic target hit. RVL-targeted ablation of PRR resulted in lower BP responses to DOCA-salt in females (WT=115±3 vs KO=104±4 mmHg; p <0.05; n=8), but not males (n=5-8), only during the first 3 days of DOCA-salt treatment. However, at day 13 of DOCA-salt treatment, female PRR RVL-KO unexpectedly exhibited exaggerated increase in systolic BP (WT=149±3 vs KO=163±3 mmHg; p =0.004; n=8) and pulse pressure (WT=31±4 vs KO=45±4 mmHg; p =0.02; n=8) when compared to control. Next, mice were challenged with an intraperitoneal hypertonic saline injection equivalent to 10% of their body weight followed by 4 hours of urine collection. Urinary sodium excretion in female PRR RVL-KO was significantly lower when compared to WT ( p <0.05). These data indicate that the role of PRR in the RVL is sex-dependent and biphasic. That is, PRR contributes to the pressor response during the initial stage of DOCA-salt HT in females, presumably by facilitating the generation of angiotensin peptides in the RVL, while it plays a protective role by promoting renal sodium excretion and preventing elevation of systolic BP during the maintenance stage of DOCA-salt HT. This study suggests that distinct PRR expressing cell populations might elicit diverging physiological functions within the RVL.

Fluid intake and blood pressure in children: the Salus per Aquam project.

Sodium intake is known to contribute to the development of hypertension, thus intake reduction is a cornerstone in the prevention and management of hypertension. The increase in renal sodium excretion might represent a further potential preventive and/or therapeutic opportunity. To explore the working hypothesis that an increased fluid intake can improve renal sodium handling towards a decrease in blood pressure. The SPA Project is a multicenter, observational, cross-sectional, cohort study investigating healthy children, aged 5-8 years as to sodium and fluid intake by means of urinary sodium and creatinine from multiple samples taken in different days in order to characterize them in lower/higher sodium and lower/higher fluid intake. Both SBP and DBP (by multiple office blood pressure measurements) were used as outcome measures. Three hundred and thirty-nine healthy, nonoverweight children (51.6% boys) with a median age of 5.7 years old (IQR: 5.3-6.2) participated in the study but only 223 could be analyzed. Among children with higher sodium intake, those introducing more fluids, showed a significantly lower blood pressure (both systolic and diastolic) compared with those with lower fluid intake: systolic 86.0 ± 8.5 vs. 90.0 ± 8.1 mmHg; P = 0.014 and diastolic: 53.8 ± 4.9 vs. 58.6 ± 6.6 mmHg; P < 0.0001. An increased fluid intake is associated with a reduced blood pressure possibly by increasing renal sodium excretion. We speculate that this simple, highly acceptable, inexpensive, and harmless measure might have a role in preventing and/or minimizing the epidemics of hypertension and of its related morbidities both in children and in adults.

Effects of phosphodiesterase V inhibition alone and in combination with BNP on cardiovascular and renal response to volume load in human preclinical diastolic dysfunction.

Preclinical diastolic dysfunction (PDD) results in impaired cardiorenal response to volume load (VL) which may contribute to the progression to clinical heart failure with preserved ejection fraction (HFpEF). The objective was to evaluate if phosphodiesterase V inhibition (PDEVI) alone or combination PDEVI plus B‐type natriuretic peptide (BNP) administration will correct the impaired cardiorenal response to VL in PDD. A randomized double‐blinded placebo‐controlled cross‐over study was conducted in 20 subjects with PDD, defined as left ventricular ejection fraction (LVEF) >50% with moderate or severe diastolic dysfunction by Doppler echocardiography and without HF diagnosis or symptoms. Effects of PDEVI with oral tadalafil alone and tadalafil plus subcutaneous (SC) BNP, administered prior to acute volume loading, were assessed. Tadalafil alone did not result in improvement in cardiac response to VL, as measured by LVEF, LV end diastolic volume, left atrial volume (LAV), or right ventricular systolic pressure (RVSP). Tadalafil plus SC BNP resulted in improved cardiac response to VL, with increased LVEF (4.1 vs. 1.8%, p = 0.08) and heart rate (4.3 vs. 1.6 bpm, p = 0.08), and reductions in both LAV (−4.3 ± 10.4 vs. 2.8 ± 6.6 ml, p = 0.03) and RVSP (−4.0 ± 3.0 vs. 2.1 ± 6.0 mmHg, p < 0.01) versus tadalafil alone. Plasma and urinary cyclic guanosine monophosphate (cGMP) excretion levels were higher (11.3 ± 12.3 vs. 1.7 ± 3.8 pmol/ml, 1851.0 ± 1386.4 vs. 173.4 ± 517.9 pmol/min, p < 0.01) with tadalafil plus SC BNP versus tadalafil alone. There was no improvement in renal response as measured by GFR, renal plasma flow, sodium excretion, and urine flow with tadalafil plus SC BNP compared to tadalafil alone. In subjects with PDD, tadalafil alone resulted in no improvement in cardiac adaptation, while tadalafil and SC BNP resulted in enhanced cardiac adaptation to VL.Trial RegistrationClinicalTrials.gov NCT01544998.

Mechanisms and consequences of casein kinase II and ankyrin-3 regulation of the epithelial Na+ channel

Activity of the Epithelial Na+ Channel (ENaC) in the distal nephron fine-tunes renal sodium excretion. Appropriate sodium excretion is a key factor in the regulation of blood pressure. Consequently, abnormalities in ENaC function can cause hypertension. Casein Kinase II (CKII) phosphorylates ENaC. The CKII phosphorylation site in ENaC resides within a canonical “anchor” ankyrin binding motif. CKII-dependent phosphorylation of ENaC is necessary and sufficient to increase channel activity and is thought to influence channel trafficking in a manner that increases activity. We test here the hypothesis that phosphorylation of ENaC by CKII within an anchor motif is necessary for ankyrin-3 (Ank-3) regulation of the channel, which is required for normal channel locale and function, and the proper regulation of renal sodium excretion. This was addressed using a fluorescence imaging strategy combining total internal reflection fluorescence (TIRF) microscopy with fluorescence recovery after photobleaching (FRAP) to quantify ENaC expression in the plasma membrane in living cells; and electrophysiology to quantify ENaC activity in split-open collecting ducts from principal cell-specific Ank-3 knockout mice. Sodium excretion studies also were performed in parallel in this knockout mouse. In addition, we substituted a key serine residue in the consensus CKII site in β-ENaC with alanine to abrogate phosphorylation and disrupt the anchor motif. Findings show that disrupting CKII signaling decreases ENaC activity by decreasing expression in the plasma membrane. In the principal cell-specific Ank-3 KO mouse, ENaC activity and sodium excretion were significantly decreased and increased, respectively. These results are consistent with CKII phosphorylation of ENaC functioning as a “switch” that favors Ank-3 binding to increase channel activity.

Early ICU-acquired hypernatraemia is associated with injury severity and preceded by reduced renal sodium and chloride excretion in polytrauma patients.

To further elucidate the origin of early ICU-acquired hypernatraemia. In this retrospective single-centre study, polytrauma patients requiring ICU treatment were analysed. Forty-eight (47.5%) of 101 included polytrauma patients developed hypernatraemia within the first 7 days on ICU. They were more severely ill as described by higher SAPS III, ISS, daily SOFA scores and initial norepinephrine requirements as well as longer requirements of mechanical ventilation and ICU treatment in general. The development of hypernatraemia was neither attributable to fluid- or sodium-balances nor renal impairment. Although lower in the hypernatraemic group from day 4 onwards, median creatinine clearances were sufficiently high throughout the observation period. However, in the hypernatraemic group, urine sodium and chloride concentrations prior to the evolvement of hypernatraemia (56 (27-87) mmol/l and 39 (23-77) mmol/l) were significantly decreased when compared to i) the time after developing hypernatraemia (94 (58-134) mmol/l and 78 (36-115) mmol/l; p < 0.001) and ii) the non-hypernatraemic group in general (101 (66-143) mmol/l and 75 (47-109) mmol/l; p < 0.001). Early ICU-acquired hypernatraemia is associated with injury severity and preceded by reduced renal sodium and chloride excretion in polytrauma patients.

Gs‐DREADD Regulation of ENaC

Activity of the epithelial Na+ channel (ENaC) fine-tunes renal Na+ excretion and consequently, contributes to the normal control of blood pressure. ENaC is expressed in the apical membrane of principal cells. Importantly, ENaC is activated by the hormone vasopressin via the V2 receptor, which is coupled to the heterotrimeric Gs protein. Stimulation of the V2 receptor rapidly activates adenylyl cyclase to increase intracellular cAMP levels. We have recently developed a mouse model with targeted expression of the Gs designer receptors exclusively activated by designer drugs (DREADD) in renal principal cells (GsD). Moreover, this mouse line has a luciferase reporter downstream of a cAMP response element binding protein site. As such, it allows in vivo reporting of cAMP levels. DREADD receptors are activated by clozapine N-oxide (CNO), which normally is an inert drug with no biological activity in the absence of DREADD receptors. We test here if CNO affects the activity of ENaC to influence renal salt and water excretion in GsD mice similarly to vasopressin. In these mice, we longitudinally monitored CNO-stimulated cAMP levels in principal cells using an IVIS Lumina XR. In parallel, we quantified CNO-dependent ENaC activity and renal sodium excretion. We observed that CNO increased ENaC activity in principal cells in freshly isolated tubules from GsD mice compared to control mice. Metabolic cages experiments demonstrated that CNO treatment (0.1 mg/kg) increased cAMP levels concomitantly with reducing sodium excretion similarly to dDAVP (1 µg) in GsD mice. Finally, in COS-7 cells expressing murine ENaC tagged with YFP, CPT-cAMP increased translocation of ENaC to the plasma membrane. Here we demonstrated the utility of a new principal cell-specific Gs-DREADD mouse line. This new mouse model will be an important tool for investigating the effects of abnormal cAMP signaling in principal cells possibly informing understanding of the cellular mechanism underpinning conditions like polycystic kidney disease.

Mechanisms and Consequences of Casein Kinase II regulation of the Epithelial Sodium Channel

Activity of the Epithelial Na+ Channel, ENaC, in the distal nephron fine-tunes renal sodium excretion. Appropriate renal sodium excretion is a key factor in the normal regulation of blood pressure. Consequently, dysregulation of ENaC causes hypertension. Casein Kinase II phosphorylates ENaC. The CKII phosphorylation site within ENaC resides within a canonical “anchor” ankyrin binding motif. The binding of Ank-3 facilitates the proper membrane localization of ENaC increasing its activity. CKII-dependent phosphorylation of ENaC is necessary and sufficient to increase channel activity and influence channel trafficking in a manner that increases activity. Herein, we tested the premise that phosphorylation of ENaC by CKII within “anchor” motifs is necessary and sufficient for ankyrin-3 binding to the channel, which is required for normal channel locale and function, and the proper regulation of renal Na+ excretion and blood pressure. This was addressed by combining total internal reflection fluorescence microscopy with fluorescence recovery after photo bleaching to follow movement of ENaC toward the plasma membrane in living cells and electrophysiology of ENaC activity in split-open collecting ducts from principal cell-specific CKII and Ank3 knockout mice. We also used whole animal physiological studies of sodium excretion in knockout mice to understand the physiological consequences of CKII and Ank3 regulation of ENaC. In addition, scanning mutagenesis was used to identify key residues in the overlapping CKII and Ank3 sites in ENaC. Findings showed that disrupting CKII signaling and abrogation of the CKII phosphorylation and Ank3 binding site within ENaC decreases channel trafficking toward the plasma membrane and activity, and promotes improper sodium excretion. These results showed that the CKII phosphorylation of ENaC functions as a “switch” that favors Ank-3 binding to increase channel activity.

SYNDROME OF INAPPROPRIATE ANTIDIURETIC HORMONE SECRETION AS A SIDE EFFECT OF CHEMOTHERAPY FOR URACHAL CARCINOMA: A CASE REPORT

A 54-year-old woman was admitted to our hospital complaining of gross hematuria and difficulty urinating. Cystoscopy revealed a tumor 4 cm in size with calcification on top of the bladder. After diagnosis of urachal carcinoma by transurethral resection of the bladder, partial cystectomy with en bloc resection of the median umbilical ligament and pelvic lymphadenectomy was performed. Pathological diagnosis confirmed urachal carcinoma, pT3b, ly1, v0, pN1, RM0. TS-1 and cisplatin chemotherapy (TS-1 at 100 mg/day on days 1-21, CDDP at 60 mg/m2 on day 8) was administered. On day 13, the patient was admitted because of consciousness disorder (Glasgow Coma Scale E2V1M4). Hyponatremia (Na 109 mEq/l) and renal excretion of sodium were present and the patient was diagnosed with the syndrome of inappropriate antidiuretic hormone secretion (SIADH) induced by chemotherapy. Serum sodium level and her consciousness level gradually improved after administration of 3% saline. SIADH caused by chemotherapy containing cisplatin is a relatively rare, but potentially serious adverse effect that requires close attention.

Diuretic Activity of Indian Medicinal Plant: A Review

Diuretics are commonly defined as drugs that increase the amount of urine produced by kidney. A precise definition is that diuretics are the agent which augment the renal excretion of sodium and either chloride or bicarbonate primarily, and water excretion secondarily. The term “saluretic” is sometime used to describe a drug that increase the renal excretion of sodium and chloride ion Diuretics are responsible for increase the rate of urine flow, sodium excretion and to maintain the volume and composition of body fluids in a various clinical Disorders. But drug-induced diuresis is very much beneficial in such type of life-threatening disorders like CHF, hypertension, renal failure, Liver cirrhosis and often pregnancy toxaemia.[1] Diuretics relieve pulmonary congestion and peripheral edema. This decreases cardiac workload, oxygen demand and plasma volume, thus decreasing blood pressure. Thus, diuretics play an important role in hypertensive patients.[2] Plant medicine is commonly used in the traditional treatment of some renal diseases, and many plants are reported to possess significant diuretic activity. The diuretic activity of a number of plants used in ethno medicine as diuretic agents has been confirmed in experimental animal. [3]The progress of a polyherbal formulation is a tough job because of the large number of different chemical compounds present in the different medicinal plants.