Antidiuretic Activity Research Articles

Calcium sensing receptor exerts a negative regulatory action toward vasopressin-induced aquaporin-2 expression and trafficking in renal collecting duct.

Vasopressin (AVP) plays a major role in the regulation of water homeostasis by its antidiuretic action on the kidney, mediated by V2 receptors. An increase in plasma sodium concentration stimulates AVP release, which in turn promotes water reabsorption. Upon binding to the V2 receptors in the renal collecting duct, AVP induces the expression and apical membrane insertion of the aquaporin-2 (AQP2) water channels and subsequent water reabsorption. AVP regulates two independent mechanisms: the short-term regulation of AQP2 trafficking and long-term regulation of the total abundance of the AQP2 protein in the cells. On the other hand, several hormones, acting through specific receptors, have been reported to antagonize AVP-mediated water transport in kidney. In this respect, we previously described that high luminal Ca2+ in the renal collecting duct attenuates short-term AVP-induced AQP2 trafficking through activation of the Ca2+-sensing receptor (CaSR). This effect is due to reduction of AVP-dependent cAMP generation and possibly hydrolysis. Moreover, CaSR signaling reduces AQP2 abundance both via AQP2-targeting miRNA-137 and the proteasomal degradation pathway. This chapter summarizes recent data elucidating the molecular mechanisms underlying the physiological role of the CaSR-dependent regulation of AQP2 expression and trafficking.

Herbal tea for the treatment of Urinary diseases as Potent diuretic and Anti-inflammatory agent

The herbal tea of previously patented composition for the treatment of urinary diseases containing twelve plants (St. John's wort, Wild pansy, Horsetail field, Common heather, Elecampane i.a.) was analyzed for the qualitative composition and quantitative content of phenolic compounds. The diuretic and anti-inflammatory activity of herbal tea thick extract was assessed. The determination of phenolic compounds was carried out by high performance liquid chromatography using standards of phenolic acids and flavonoids. Diuretic activity was checked by the method of Berkhin for the dosage in the range from 100 to 700mg/kg. Level of urination was assessed during 1, 2, and 3 hours of experiment. Edema was induced with 1% carrageenan. The dosage of oral treatment was from 100 to 250mg/kg. Paw volume was checked at time equal to 1, 2, 3, 4, and 5 hours. Several groups of phenolic compounds were detected, and six substances were identified individually. The total content of phenolic compounds was 23.8mg/g, with the content of flavonoids 10.4mg/g and chlorogenic acid 2.7mg/g. The herbal tea showed diuretic activity of 100% growth at the dosage of 200mg/kg. Further increase of dosage led to antidiuretic activity. From the dosage of 500mg/kg we observed the diuretic activity again, which was the highest for the dosage of 700mg/kg showing 271% growth in relation to the control group. The antiinflammatory activity was the highest at the dosage of 200 and 250mg/kg and was equal to 25% in relation to the control group.

Diuretic and Antidiuretic Activities of Ethanol Extract and Fractions of Lagopsis supina in Normal Rats.

Lagopsis supina is a well-known traditional Chinese medicine and used as an agent for diuresis in China for centuries. This is the first time to evaluate the diuretic activity of the ethanol extract of L. supina (LS) and its four fractions (LSA, LSB, LSC, and LSD) in normal rats. After the administration of LS-H, LS-M, LSB-H, and LSC-L, the urine output of the rats was significantly increased, while the urine excretion was significantly reduced after treatment with LSB-L. The urine Na+ excretion was remarkably increased with LS-H, LS-M, LSA-H, LSA-L, LSB-H, LSC-L, and LSD-L, and the urine K+ excretion was significantly increased after administration of LS-H and LSB-H. Moreover, the urine Na+ and K+ excretion was significantly reduced after treatment with LSC-H and LSD-H. However, the urine pH values and urine and serum Na+-K+-ATPase levels did not show remarkable change after administration of LS or its four fractions in comparison with the control group. On the contrary, LS and its four fractions can suppress the renin-angiotensin-aldosterone system (RAAS), including ADH arrest by LSB-H, LSB-L, LSC-L, LSD-L, and LSD-H and ALD arrest by LSD-L, as well as promote ANP release by LS-M, LSB-H, LSC-H, and LSD-H, while furosemide can suppress only arrest of ADH within 24 h compared with the control group. In addition, LS and its four fractions did not change the urine and serum TNF-α and IL-6 levels in normal rats within 24 h. This study will provide a quantitative basis for explaining the natural medicinal use of LS as a diuretic agent for edema and promoting the diuretic process.

Дослідження впливу екстрактів листя шавлії лікарської на діурез у щурів

Відомо, що шавлія лікарська (ШЛ) має виражений протизапальний ефект, який можна порівняти з таким у нестероїдних протизапальних препаратів. Доцільним є з’ясування впливу екстрактів ШЛ на сечовидільну функцію нирок. Мета дослідження – вивчення впливу 11 різних екстрактів ШЛ на діурез у щурів за умов водного навантаження. Дослідження виконано за стандартною методикою Є. Б. Берхіна. Досліджувані екстракти вводили внутрішньошлунково (в/ш) в дозах 10, 15, 20, 50, 70 мг/кг (екстракти № 1, 2 і 3) і 10, 20, 50, 70 мг/ кг (екстракти № 4, 5, 6, 7, 8, 9, 10 і 11). Препарати порівняння – фуросемід (10 мг/кг, в/ш), гідрохлортіазид (50 мг/кг, в/ш), адіурекрин (2 ОД, підшкірно). Білих нелінійних щурів розподіляли в групи по 6 тварин. Діурез реєстрували через 2 і 4 год після водного навантаження. За результатами дослідження встановлено, що 10 з 11 екстрактів ШЛ виявляють антидіуретичні властивості. Досліджувані сполуки статистично значущо зменшували об’єм виведеної сечі на 15,7– 58,3 % порівняно з показником контрольних тварин (р < 0,05). Для екстрактів № 1, 2, 3, 6, 8, 9, 10 і 11 встановлено зворотний дозозалежний ефект, тобто, у разі зменшення дози (до 10–20 мг/кг) посилювалась антидіуретична дія. На відміну від цих екстрактів, екстракти № 4 і 5 виявляли антидіуретичну активність у всьому діапазоні досліджуваних доз (10–70 мг/кг). Екстракт № 7 у жодній з досліджуваних доз не чинив антидіуретичного ефекту. Зважаючи на те, що основним компонентом екстрактів ШЛ є фенольні сполуки, зокрема, гідроксикоричні кислоти, зроблено припущення, що в основі антидіуретичного ефекту є їхня здатність зменшувати синтез простагландинів. Амінокислоти L-лізин і L-аргінін у цьому випадку проявили потенціювальний ефект.

Vasopressin actions in the kidney renin angiotensin system and its role in hypertension and renal disease.

Vasopressin, also named antidiuretic hormone (ADH), arginine vasopressin (AVP) is the main hormone responsible for water maintenance in the body through the antidiuretic actions in the kidney. The posterior pituitary into the blood releases vasopressin formed in the hypothalamus. Hypothalamic osmotic neurons are responsible to initiate the cascade for AVP actions. The effects of AVP peptide includes activation of V2 receptors which stimulate the formation of cyclic AMP (cAMP) and phosphorylation of water channels aquaporin 2 (AQP2) in the collecting duct. AVP also has vasoconstrictor effects through V1a receptors in the vasculature, while V1b is found in the nervous system. V1a and b receptors increases intracellular Ca2+ while activation of V2 receptors of signaling pathways are related to cAMP-dependent phosphorylation in kidney collecting ducts acting in coordination to stimulate water and electrolyte homeostasis. AVP potentiate formation of intratubular angiotensin II (Ang II) through V2 receptors-dependent distal tubular renin formation, contributing to Na+ reabsorption. On the same way, Ang II receptors are able to potentiate the effects of V2-dependent stimulation of AQP2 abundance in the plasma membrane. The role of AVP in hypertension and renal disease has been demonstrated in pathological states with the involvement of V2 receptors in the progression of kidney damage in diabetes and also on the stimulation of intracellular pathways linked to the development of polycystic kidney.

Urine Osmolality and Renal Outcome in Patients with Chronic Kidney Disease: Results from the KNOW-CKD

Background: Urine osmolality indicates the ability of the kidney to concentrate the urine and reflects the antidiuretic action of vasopressin. However, results about the association between urine osmolality and adverse renal outcomes in chronic kidney disease (CKD) are conflicting. We investigated the association between urine osmolality and adverse renal outcomes in a nationwide prospective CKD cohort. Methods: A total of 1,999 CKD patients were categorized into 3 groups according to their urine osmolality tertiles. Primary outcome was a composite of 50% decline in the estimated glomerular filtration rate (eGFR), initiation of dialysis, or kidney transplantation. Results: During a mean follow-up of 35.2 ± 19.0 months, primary outcome occurred in 432 (21.6%) patients; 240 (36.4%), 162 (24.3%), and 30 (4.5%) in the lowest, middle, and highest tertiles, respectively. Low urine osmolality was independently associated with a greater risk of CKD progression (hazard ratio [HR], 1.71; 95% confidence interval [CI], 1.12–2.59). This association was particularly evident in patients with CKD stages 3–4 (per 10 mosm/kg decrease; HR, 1.02; 95% CI, 1.00–1.03). Adding urine osmolality to a base model with conventional factors significantly increased the ability to predict CKD progression (C-statistics, 0.86; integrated discrimination improvement [IDI], 0.021; both p < 0.001). However, adding both urine osmolality and eGFR did not further improve the predictive ability compared with the addition of eGFR only (C-statistics, p = 0.29; IDI, p = 0.09). Conclusions: Low urine osmolality was an independent risk factor for adverse renal outcomes in CKD patients, but its predictive ability did not surpass eGFR. Thus, kidney function should be considered while interpreting the clinical significance of urine osmolality.

Renal V1A Receptor Does Not Increase Na+ Excretion in the Rat Isolated Kidney Perfused at Constant Pressure

The effect of arginine vasopressin (AVP) on Na+ excretion has been the subject of many studies and is still a matter of debate. While AVP given at physiological doses was shown to enhance Na+ excretion in water‐loaded rats, others have shown that AVP‐induced natriuresis occurred at doses associated with increases in mean arterial pressure, suggesting that pressure natriuresis may be the underlying mechanism. This natriuresis is thought to be mediated by the V1A receptor (V1AR). To investigate if the renal V1AR mediates natriuresis, we employed the rat isolated kidney perfused at constant pressure to assess the effect of the selective V1AR agonist, [Phe2, Ile3, Orn8]‐vasopressin, on various parameters. Specifically, we sought to test the hypothesis that selective activation of V1AR in the kidney increases urinary excretion of Na+.Each isolated kidney was perfused for a total of 85 min, starting with 10 min for equilibration, and followed by five 15 min‐periods with ascending concentrations of the agonist (0, 30, 100, 300, and 1000 pM). Time‐control kidneys were perfused with media without the agonist for the entire 85 min.We found that the agonist increased renal vascular resistance in a concentration‐dependent manner without changing GFR. At the highest concentrations, the agonist showed antidiuretic activity characterized by decreased urine flow rate and effective water clearance, and increased urine osmolality. Our results further show that although there was an increase in absolute Na+ excretion and fractional excretion Na+, no difference was observed between treated‐ and control‐kidneys, suggesting that the changes in Na+ handling were inherent to perfusion itself rather than activation of the renal V1AR.We conclude that AVP‐induced natriuresis may not be mediated by the renal V1AR, and that AVP may induce natriuresis indirectly through extrarenal factors lacking in the isolated kidney.Support or Funding InformationFerring Research Institute, Inc., San Diego, CAThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Anti-diuretic action of a CAPA neuropeptide against a subset of diuretic hormones in the disease vector Aedes aegypti.

The mosquito Aedes aegypti is a vector responsible for transmitting various pathogens to humans, and their prominence as chief vectors of human disease is largely due to their anthropophilic blood feeding behaviour. Larval stage mosquitoes must deal with the potential dilution of their haemolymph in freshwater, whereas the haematophagus A. aegypti female faces the challenge of excess ion and water intake after a blood meal. The excretory system, composed of the Malpighian tubules (MTs) and hindgut, is strictly controlled by neuroendocrine factors, responsible for the regulation of diuresis across all developmental stages. The highly studied insect MTs are influenced by a variety of diuretic hormones and, in some insects, anti-diuretic factors. In the present study, we investigated the effects of AedaeCAPA-1 neuropeptide on larval and adult female A. aegypti MTs stimulated with various diuretic factors including serotonin (5-HT), a corticotropin-related factor (CRF) diuretic peptide, a calcitonin-related diuretic hormone (DH31) and a kinin-related diuretic peptide. Overall, our findings establish that AedaeCAPA-1 specifically inhibits secretion of larval and adult MTs stimulated by 5-HT and DH31, whilst having no activity on MTs stimulated by other diuretic factors. Furthermore, although AedaeCAPA-1 acts as an anti-diuretic, it does not influence the relative proportions of cations transported by adult MTs, thus maintaining the kaliuretic activity of 5-HT and natriuretic activity of DH31 In addition, we tested the effects of the second messenger cGMP in adult MTs. We established that cGMP has similar effects to AedaeCAPA-1, strongly inhibiting 5-HT- and DH31-stimulated fluid secretion, but with only minor effects on CRF-stimulated diuresis. Interestingly, although AedaeCAPA-1 has no inhibitory activity on kinin-stimulated fluid secretion, cGMP strongly inhibited fluid secretion by this diuretic hormone, which targets stellate cells specifically. Collectively, these results support that AedaeCAPA-1 inhibits select diuretic factors acting on the principal cells and this probably involves cGMP as a second messenger. Kinin-stimulated diuresis, which targets stellate cells, is also inhibited by cGMP, suggesting that another anti-diuretic factor in addition to AedaeCAPA-1 exists and may utilize cGMP as a second messenger.

Hereditary Nephrogenic Diabetes Insipidus: Pathophysiology and Possible Treatment. An Update.

Under physiological conditions, excessive loss of water through the urine is prevented by the release of the antidiuretic hormone arginine-vasopressin (AVP) from the posterior pituitary. In the kidney, AVP elicits a number of cellular responses, which converge on increasing the osmotic reabsorption of water in the collecting duct. One of the key events triggered by the binding of AVP to its type-2 receptor (AVPR2) is the exocytosis of the water channel aquaporin 2 (AQP2) at the apical membrane the principal cells of the collecting duct. Mutations of either AVPR2 or AQP2 result in a genetic disease known as nephrogenic diabetes insipidus, which is characterized by the lack of responsiveness of the collecting duct to the antidiuretic action of AVP. The affected subject, being incapable of concentrating the urine, presents marked polyuria and compensatory polydipsia and is constantly at risk of severe dehydration. The molecular bases of the disease are fully uncovered, as well as the genetic or clinical tests for a prompt diagnosis of the disease in newborns. A real cure for nephrogenic diabetes insipidus (NDI) is still missing, and the main symptoms of the disease are handled with s continuous supply of water, a restrictive diet, and nonspecific drugs. Unfortunately, the current therapeutic options are limited and only partially beneficial. Further investigation in vitro or using the available animal models of the disease, combined with clinical trials, will eventually lead to the identification of one or more targeted strategies that will improve or replace the current conventional therapy and grant NDI patients a better quality of life. Here we provide an updated overview of the genetic defects causing NDI, the most recent strategies under investigation for rescuing the activity of mutated AVPR2 or AQP2, or for bypassing defective AVPR2 signaling and restoring AQP2 plasma membrane expression.

Abstract P236: Site-1 Protease-derived Soluble (Pro) Renin Receptor Mediates Angiotensin II-induced Hypertension via Activation of Intrarenal Renin System

We have previously shown that collecting duct (CD)-specific deletion of (pro)renin receptor (PRR) attenuates angiotensin II (Ang II)-induced hypertension, accompanied with reduced soluble PRR (sPRR) that exerts antidiuretic action. Recent preliminary and published results demonstrated site-1portease (S1P) but not furin or ADMA19 as the predominant PPR cleavage enzyme. In the present study, we evaluated involvement of S1P-derived sPRR in Ang II-induced hypertension. By radiotelemetry, CD PRR KO mice exhibited reduced MAP on day 7 of Ang II infusion at 300 ng/kg/min as compared with floxed mice (MAP: 118±5 vs. 137±3 mmHg, N=5, p&lt;0.05). Administration of sPRR-His, a histidine-tagged sPRR, at 120 μg/kg/d via i.v. infusion to CD PRR KO mice for additional 7 days largely restored the sensitivity to Ang II (MAP: 139±6 mmHg in sPRR-His +Ang II group vs. 116±5 mmHg in Ang II group, N = 4, p&lt;0.05). The i.v. infusion was achieved via placement of a catheter in jugular vein with the other end connected to mimipump. In C57/BL6 mice, administration of a S1P inhibitor PF429242 (PF) via mini pump infusion at 30 mg/kg/d for 7 days attenuated Ang II-induced increases in MAP (day 7: 125±5 in Ang II+ PF group vs. 142±3 in Ang II group; N=6, p&lt;0.05), urinary sPRR excretion (27±4 vs. 63±9 pg/24h; N=6, p&lt;0.05). In parallel, urinary renin levels were elevated by Ang II, which was blunted by PF (renin activity: 0.17±0.03 in Ang II+PF vs. 0.80±0.081 in Ang II vs. 0.12±0.016 ng/24h in Control, N=6, p&lt;0.01; active renin content: 15.2±2.7 vs. 236.0±23.2 vs. 5.6±1.3 ng/24h, N=6, p&lt;0.01; prorenin content: 9.6±3.1 vs. 27.8±6.1 vs. 6.2±1.8 ng/24h, N=6, p&lt;0.05; total renin content: 24.8±5.2 vs. 263.8±27.0 vs. 11.8±3.0 ng/24h, N=6, p&lt;0.01). An intravenous infusion of sPRR-His counteracted the blood pressure-lowering effect of PF in Ang II-infused mice (MAP: 147±3 in PF+sPRR vs. 126±4 mmHg in PF; N=4, p&lt;0.05). Together, these results suggest that S1P-derived sPRR contributes to Ang II-induced hypertension through activation of intrarenal renin-angiotensin system.

Vasopressin: physiology, assessment and osmosensation.

Vasopressin (AVP) plays a major role in the regulation of water and sodium homeostasis by its antidiuretic action on the kidney, mediated by V2 receptors. AVP secretion is stimulated by a rise in plasma osmolality, a decline in blood volume or stress. V1a receptors are expressed in vascular smooth muscle cells, but the role of vasopressin in blood pressure regulation is still a matter of debate. AVP may also play a role in some metabolic pathways, including gluconeogenesis, through its action on V1a receptors expressed in the liver. It is now understood that thirst and arginine vasopressin (AVP) release are regulated not only by the classical homeostatic, intero-sensory plasma osmolality negative feedback, but also by novel, extero-sensory, anticipatory signals. AVP measurement is time-consuming, and AVP level in the blood in the physiological range is often below the detection limit of the assays. Recently, an immunoassay has been developed for the measurement of copeptin, a fragment of the pre-provasopressin molecule that is easier to measure. It has been shown to be a good surrogate marker of AVP.

The Effect of Long Term use of Glibenclamide on Serum and Urinary Sodium and Potassium Level in Type 2 DM Patients

Long-term use of sulfonylureas including chlorpropamide, is known to potentiate the antidiuretic action of arginine vasopressin (AVP), predisposing to hyponatremia.The present study was designed to evaluate the effect of long term use of glibenclamide on serum and urinary levels of sodium and potassium in Type 2 DM patients in Iraqi DM centers. Ninety eight patients with Type 2 DM who were maintained on different doses of glibenclamide for at least 1 year, attending the centre for Diabetes and Endocrinology in Al-Rusafa, Baghdad, were enrolled in the study, in addition to 15 normal healthy subjects. Patients were allocated into three groups according to the dose of glibenclamide that they received. Blood and urine samples were obtained for evaluation of sodium and potassium levels in these samples by flamephotometry. The results indicated that glibenclamide use resulted in significant elevation in serum levels of sodium and potassium compared to controls, while urinary excretion of these cations was not significantly changed. Stratification of patients according to the dose of glibenclamide revealed that this effect on sodium and potassium was not dose dependent. In conclusion, long term use of glibenclamide impairs normal values of Sodium and potassium independent of the administered dose. &#x0D; Key words: Glibenclamide, sodium, potassium.

A Novel Mutation in the AVPR2 Gene in a Palestinian Family with Nephrogenic Diabetes Insipidus

AbstractNephrogenic diabetes insipidus (NDI) is a urinary concentrating defect resulting from resistance of the collecting duct to the antidiuretic action of vasopressin (AVP). The X-linked recessive form is the most frequent genetic cause of inherited NDI and can be caused by mutations in the gene encoding the V2 vasopressin receptor (AVPR2). A Palestinian male infant presented in the neonatal period with failure to thrive, vomiting, irritability, fever, and polyuria, and had biochemical findings consistent with NDI. The diagnosis of NDI was established based on the clinical picture, absent response to desmopressin, and a similarly affected elder brother. Sequencing of the AVPR2 gene for the patient and his affected brother revealed a novel missense mutation with replacement of G by A in codon 82 located in exon 2 (TGC → TAC), causing a cysteine to tyrosine substitution (C82Y). Testing of the mother showed that she was the carrier of that mutation. This is the identified AVPR2 mutation in a Palestinian family. Knowledge of these mutations will allow genetic counseling and early diagnosis of affected males.

DIURETIC AND ANTI-DIURETIC BIOACTIVITY DIFFERENCES OF THE SEED AND SHELL EXTRACTS OF ALPINIA OXYPHYLLA FRUIT.

Background:Alpinia oxyphylla fruit (AOF, Yizhi in Chinese) is a well-known traditional Chinese medicine as an anti-diuretic agent and composed of two parts i.e. seed and shell. These two parts have different components, but the bioactivity differences of the two parts are not clear. This study aims to evaluate the different anti-diuretic effects of the seed and shell of AOF.Materials and Methods:The potential bioactive components were analyzed by UPLC-Q-TOF-MS. The diuretic and anti-diuretic activity was determined with saline-loads rats.Results:The results showed that the 200 mg/kg and 400mg/kg of SREAO displayed a short-time anti-diuretic activity 1h after administration and then a significant diuretic activity was being observed at 5-6 h in 400mg/kg group of SREAO. And the 400mg/kg doses of SREAO also showed a remarkable increase for electrolyte excretion of K+. Three sesquiterpene compounds, namely oxyphyllol A (1), oxyphyllol B (2), and nootkatone (3) were identified from the active SREAO fraction by UHPLC-ESI-Q-TOF/MS.Conclusion:The seed part of Alpinia oxyphylla possessed pronounced diuretic and anti-diuretic effect. The sesquiterpene components are the major constituents and possibly contributed the diuretic and anti-diuretic activity.

Potent antidiuretic agonists, deamino-vasopressin and desmopressin, and their inverso analogs: NMR structure and interactions with micellar and liposomic models of cell membrane.

Deamination of vasopressin (AVP) enhances its antidiuretic activity. Moreover, introduction of D-Arg8 instead of its L enantiomer in deamino-vasopressin (dAVP) results in an extremely potent and selective antidiuretic agonist - desmopressin (dDAVP). In this study we describe the synthesis, pharmacological properties and structures of these two potent antidiuretic agonists, and their inverso analogs. The structures of the peptides are studied in micellar and liposomic models of cell membrane using CD spectroscopy. Additionally, three-dimensional structures in mixed anionic-zwitterionic micelles are obtained using NMR spectroscopy supported by molecular dynamics simulations. Our conformational studies have shown that desmopressin in a membrane mimicking environment adopts one of the characteristic for vasopressin-like peptides β-turn - in position 3,4. Furthermore, dDAVP shows the tendency to create a β-turn in the Cys6-Gly9 C-tail, considered to be important for the antidiuretic activity, and also some tendency to adopt a 5,6 β-turn. In desmopressin, in contrast to the native vasopressin, deamino-vasopressin and [D-Arg8]-vasopressin (DAVP), the Arg8 side chain, crucial for the pressor and antidiuretic activities, is very well exposed for interaction with the receptor, whereas Gly9, crucial for the pressor and uterotonic activities, is situated together with the C-terminal amide group very close to the tocin ring. The arrangements of the Gln4 and Asn5 side chains, being crucial for OT activity, also differ in desmopressin as compared to those of AVP, dAVP and DAVP. These differences in arrangement of the important for activities side chains are likely to explain extremely potent and selective antidiuretic activities of desmopressin. © 2016 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 106: 245-259, 2016.

Antidiuretic Action of Collecting Duct (Pro)Renin Receptor Downstream of Vasopressin and PGE2 Receptor EP4.

Within the kidney, the (pro)renin receptor (PRR) is predominantly expressed in the collecting duct (CD), particularly in intercalated cells, and it is regulated by the PGE2 receptor EP4 Notably, EP4 also controls urinary concentration through regulation of aquaporin 2 (AQP2). Here, we tested the hypothesis that sequential activation of EP4 and PRR determines AQP2 expression in the CD, thus mediating the antidiuretic action of vasopressin (AVP). Water deprivation (WD) elevated renal PRR expression and urinary soluble PRR excretion in rats. Intrarenal infusion of a PRR decoy peptide, PRO20, or an EP4 antagonist partially prevented the decrease in urine volume and the increase in urine osmolality and AQP2 expression induced by 48-hour WD. In primary cultures of rat inner medullary CD cells, AQP2 expression induced by AVP treatment for 24 hours depended on sequential activation of the EP4 receptor and PRR. Additionally, mice lacking PRR in the CD exhibited increased urine volume and decreased urine osmolality under basal conditions and impaired urine concentrating capability accompanied by severe volume loss and a dangerous level of plasma hyperosmolality after WD. Together, these results suggest a previously undescribed linear AVP/PGE2/EP4/PRR pathway in the CD for regulation of AQP2 expression and urine concentrating capability.

Soluble (pro)renin receptor via β-catenin enhances urine concentration capability as a target of liver X receptor

The extracellular domain of the (pro)renin receptor (PRR) is cleaved to produce a soluble (pro)renin receptor (sPRR) that is detected in biological fluid and elevated under certain pathological conditions. The present study was performed to define the antidiuretic action of sPRR and its potential interaction with liver X receptors (LXRs), which are known regulators of urine-concentrating capability. Water deprivation consistently elevated urinary sPRR excretion in mice and humans. A template-based algorithm for protein-protein interaction predicted the interaction between sPRR and frizzled-8 (FZD8), which subsequently was confirmed by coimmunoprecipitation. A recombinant histidine-tagged sPRR (sPRR-His) in the nanomolar range induced a remarkable increase in the abundance of renal aquaporin 2 (AQP2) protein in primary rat inner medullary collecting duct cells. The AQP2 up-regulation relied on sequential activation of FZD8-dependent β-catenin signaling and cAMP-PKA pathways. Inhibition of FZD8 or tankyrase in rats induced polyuria, polydipsia, and hyperosmotic urine. Administration of sPRR-His alleviated the symptoms of diabetes insipidus induced in mice by vasopressin 2 receptor antagonism. Administration of the LXR agonist TO901317 to C57/BL6 mice induced polyuria and suppressed renal AQP2 expression associated with reduced renal PRR expression and urinary sPRR excretion. Administration of sPRR-His reversed most of the effects of TO901317. In cultured collecting duct cells, TO901317 suppressed PRR protein expression, sPRR release, and PRR transcriptional activity. Overall we demonstrate, for the first time to our knowledge, that sPRR exerts antidiuretic action via FZD8-dependent stimulation of AQP2 expression and that inhibition of this pathway contributes to the pathogenesis of diabetes insipidus induced by LXR agonism.

Pharmacognostical, Phytochemical and Pharmacological Overview: Cissus quadrangularis Linn.

Cissus quadrangularis (Linn) has been used by the common man in India, and neighboring countries, Pakistan, Sri Lanka, Malaysia for promotion of fracture healing and well known as “Hadjod”. It is also known as Vitis quadrangularis Wall. belongs to family Vitaceae. It is a common perennial climber, which is distributed throughout India, particularly in tropical regions. It requires warm tropical climate and propagated by stem cuttings. The plant is prescribed in the ancient Ayurvedic literature as a general tonic and analgesic, with specific bone fracture healing properties. The plant is believed to be useful in helminthiasis, anorexia, dyspepsia, colic, flatulence, skin diseases, leprosy, hemorrhage, epilepsy, convulsion, haemoptysis, tumors, chronic ulcers, swellings. The scrutiny of the present overview revealed pharmacognostical, phytochemical and some notable pharmacological activities of the plant such as Anti-osteoporotic activity, antioxidant, free radical scavenging, antimicrobial, antibacterial, bone healing, anti ulcer, analgesic and anti inflammatory, diuretic, Anabolic and Androgenic activity and toxicity studies.

Arginine-, D-arginine-vasopressin, and their inverso analogues in micellar and liposomic models of cell membrane: CD, NMR, and molecular dynamics studies.

We describe the synthesis, pharmacological properties, and structures of antidiuretic agonists, arginine vasopressin (AVP) and [d-Arg8]-vasopressin (DAVP), and their inverso analogues. The structures of the peptides are studied based on micellar and liposomic models of cell membranes using CD spectroscopy. Additionally, three-dimensional structures in mixed anionic–zwitterionic micelles are obtained using NMR spectroscopy and molecular dynamics simulations. NMR data have shown that AVP and DAVP tend to adopt typical of vasopressin-like peptides β-turns: in the 2–5 and 3–6 fragments. The inverso-analogues also adopt β-turns in the 3–6 fragments. For this reason, their inactivity seems to be due to the difference in side chains orientations of Tyr2, Phe3, and Arg8, important for interactions with the receptors. Again, the potent antidiuretic activity of DAVP can be explained by CD data suggesting differences in mutual arrangement of the aromatic side chains of Tyr2 and Phe3 in this peptide in liposomes rather than of native AVP. In the presence of liposomes, the smallest conformational changes of the peptides are noticed with DPPC and the largest with DPPG liposomes. This suggests that electrostatic interactions are crucial for the peptide–membrane interactions. We obtained similar, probably active, conformations of the antidiuretic agonists in the mixed DPC/SDS micelles (5:1) and in the mixed DPPC/DPPG (7:3) liposomes. Thus it can be speculated that the anionic–zwitterionic liposomes as well as the anionic–zwitterionic micelles, mimicking the eukaryotic cell membrane environment, partially restrict conformational freedom of the peptides and probably induce conformations resembling those of biologically relevant ones.Electronic supplementary materialThe online version of this article (doi:10.1007/s00249-015-1071-4) contains supplementary material, which is available to authorized users.

Selective V₂-Agonist of Vasopressin Desmopressin Stimulates Activity of Serum Hyaluronidase.

Effects of desmopressin (arginine vasopressin V2 receptor agonist) were studied for elucidation of the possible role of the kidneys in the regulation of blood hyaluronidase activity. Similar to vasopressin, intraperitoneal administration of desmopressin to Wistar rats increased blood hyaluronidase activity by 30%. Against the background of water load, nether desmopressin nor vasopressin increased blood hyaluronidase activity. The possibility of renal secretion of hyaluronidase into the blood as a mechanism of antidiuretic activity of vasopressin and its role in the regulation of water metabolism are discussed.