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High concentrations of urinary calcium counteract vasopressin action via the activation of the Calcium‐Sensing Receptor (CaSR) expressed in the luminal membrane of the collecting duct cells, which impairs the trafficking of aquaporin‐2 (AQP2). In line with these findings, we provide evidence that, with respect to wild‐type mice, CaSR knock‐in (KI) mice mimicking autosomal dominant hypocalcaemia, display a significant decrease in the total content of AQP2 associated with significantly higher levels of AQP2 phosphorylation at Ser261, a phosphorylation site involved in AQP2 degradation. Interestingly, KI mice also had significantly higher levels of phosphorylated p38MAPK, a downstream effector of CaSR and known to phosphorylate AQP2 at Ser261. Moreover, ATF1 phosphorylated at Ser63, a transcription factor downstream of p38MAPK, was significantly higher in KI. In addition, KI mice had significantly higher levels of AQP2‐targeting miRNA137 consistent with a post‐transcriptional downregulation of AQP2. In vivo treatment of KI mice with the calcilytic JTT‐305, a CaSR antagonist, increased AQP2 expression and reduced AQP2‐targeting miRNA137 levels in KI mice. Together, these results provide direct evidence for a critical role of CaSR in impairing both short‐term vasopressin response by increasing AQP2‐pS261, as well as AQP2 abundance, via the p38MAPK‐ATF1‐miR137 pathway. Key points: Calcium‐Sensing Receptor (CaSR) activating mutations are the main cause of autosomal dominant hypocalcaemia (ADH) characterized by inappropriate renal calcium excretion leading to hypocalcaemia and hypercalciuria. Current treatments of ADH patients with parathyroid hormone, although improving hypocalcaemia, do not improve hypercalciuria or nephrocalcinosis.In vivo treatment with calcilytic JTT‐305/MK‐5442 ameliorates most of the ADH phenotypes of the CaSR knock‐in mice including hypercalciuria or nephrocalcinosis and reverses the downregulation of the vasopressin‐sensitive aquaporin‐2 (AQP2) expression, providing direct evidence for a critical role of CaSR in impairing vasopressin response.The beneficial effect of calcilytic in reducing the risk of renal calcification may occur in a parathyroid hormone‐independent action through vasopressin‐dependent inhibition of cAMP synthesis in the thick ascending limb and in the collecting duct.The amelioration of most of the abnormalities in calcium metabolism including hypercalciuria, renal calcification, and AQP2‐mediated osmotic water reabsorption makes calcilytic a good candidate as a novel therapeutic agent for ADH. [ABSTRACT FROM AUTHOR]

Nephrogenic syndrome of inappropriate antidiuresis (NSIAD) is a rare X‐linked disease caused by gain‐of‐function mutations of arginine vasopressin receptor 2 (V2R). Patients with NSIAD are characterized by the inability to excrete a free water load and by inappropriately increased urinary osmolality despite very low levels of plasma vasopressin, resulting in euvolaemic hyponatraemia. To dissect the signalling downstream V2R constitutively active variants, Flp‐In T‐REx Madin‐Darby canine kidney (FTM) cells, stably transfected with V2R mutants (R137L, R137C and F229V) and AQP2‐wt or non‐phosphorylatable AQP2‐S269A/AQP2‐S256A, were used as cellular models. All three activating V2R mutations presented constitutive plasma membrane expression of AQP2‐wt and significantly higher basal water permeability. In addition, V2R‐R137L/C showed significantly higher activity of Rho‐associated kinase (ROCK), a serine/threonine kinase previously suggested to be involved in S269‐AQP2 phosphorylation downstream of these V2R mutants. Interestingly, FTM cells expressing V2R‐R137L/C mutants and AQP2‐S269A showed a significant reduction in AQP2 membrane abundance and a significant reduction in ROCK activity, indicating the crucial importance of S269‐AQP2 phosphorylation in the gain‐of‐function phenotype. Conversely, V2R‐R137L/C mutants retained the gain‐of‐function phenotype when AQP2‐S256A was co‐expressed. In contrast, cells expressing the F229V mutant and the non‐phosphorylatable AQP2‐S256A had a significant reduction in AQP2 membrane abundance along with a significant reduction in basal osmotic water permeability, indicating a crucial role of Ser256 for this mutant. These data indicate that the constitutive AQP2 trafficking associated with the gain‐of‐function V2R‐R137L/C mutants causing NSIAD is protein kinase A independent and requires an intact Ser269 in AQP2 under the control of ROCK phosphorylation. Key points: Nephrogenic syndrome of inappropriate antidiuresis is caused by two constitutively active variant phenotypes of AVPR2, one sensitive to vaptans (V2R‐F229V) and the other vaptan resistant (V2R‐R137C/L). In renal cells, all three activating arginine vasopressin receptor 2 (V2R) variants display constitutive AQP2 plasma membrane expression and high basal water permeability.In cells expressing V2R‐R137L/C mutants, disruption of the AQP2‐S269 phosphorylation site caused the loss of the gain‐of‐function phenotype, which, in contrast, was retained in V2R‐F229V‐expressing cells.Cells expressing the V2R‐F229V mutant were instead sensitive to disruption of the AQP2‐S256 phosphorylation site.The serine/threonine kinase Rho‐associated kinase (ROCK) was found to be involved in AQP2‐S269 phosphorylation downstream of the V2R‐R137L/C mutants.These findings might have clinical relevance for patients with nephrogenic syndrome of inappropriate antidiuresis. [ABSTRACT FROM AUTHOR]

Acute pyelonephritis (APN) is most frequently caused by uropathogenic Escherichia coli (UPEC), which ascends from the bladder to the kidneys during a urinary tract infection. Patients with APN have been reported to have reduced renal concentration capacity under challenged conditions, polyuria, and increased aquaporin-2 (AQP2) excretion in the urine. We have recently shown increased AQP2 accumulation in the plasma membrane in cell cultures exposed to E. coli lysates and in the apical plasma membrane of inner medullary collecting ducts in a 5-day APN mouse model. This study aimed to investigate if AQP2 expression in host cells increases UPEC infection efficiency and to identify specific bacterial components that mediate AQP2 plasma membrane insertion. As the transepithelial water permeability in the collecting duct is codetermined by AQP3 and AQP4, we also investigated whether AQP3 and AQP4 localization is altered in the APN mouse model. We show that AQP2 expression does not increase UPEC infection efficiency and that AQP2 was targeted to the plasma membrane in AQP2-expressing cells in response to the two pathogen-associated molecular patterns (PAMPs), lipopolysaccharide and peptidoglycan. In contrast to AQP2, the subcellular localizations of AQP1, AQP3, and AQP4 were unaffected both in lysate-incubated cell cultures and in the APN mouse model. Our finding demonstrated that cellular exposure to lipopolysaccharide and peptidoglycan can trigger the insertion of AQP2 in the plasma membrane revealing a new regulatory pathway for AQP2 plasma membrane translocation, which may potentially be exploited in intervention strategies. NEW & NOTEWORTHY: Acute pyelonephritis (APN) is associated with reduced renal concentration capacity and increased aquaporin-2 (AQP2) excretion. Uropathogenic Escherichia coli (UPEC) mediates changes in the subcellular localization of AQP2 and we show that in vitro, these changes could be elicited by two pathogen-associated molecular patterns (PAMPs), namely, lipopolysaccharide and peptidoglycan. UPEC infection was unaltered by AQP2 expression and the other renal AQPs (AQP1, AQP3, and AQP4) were unaltered in APN. [ABSTRACT FROM AUTHOR]

The text is an editorial discussing the 72nd Annual Meeting of the Italian Society of Physiology, which brought together leading physiologists to discuss innovative research directions. The meeting covered a wide range of topics, including cell physiology, neurobiology, and cardiovascular health. Some notable findings presented at the meeting include the potential therapeutic use of autophagy modulation in neurological disorders, the protective effects of botanical extracts and dietary supplements against oxidative stress-related pathologies, the role of cellular communication in disease pathogenesis and therapeutic interventions, and the impact of environmental pollutants on human health. The editorial emphasizes the importance of collaboration and curiosity in advancing scientific knowledge and expresses gratitude to the authors, reviewers, and contributors who made the research topic possible. [Extracted from the article]

Although we have sent humans into space for more than 50 years crucial questions regarding kidney physiology, volume regulation and osmoregulation remain unanswered. The complex interactions between the renin-angiotensin-aldosterone system, the sympathetic nervous system, osmoregulatory responses, glomerular function, tubular function, and environmental factors such as sodium and water intake, motion sickness and ambient temperature make it difficult to establish the exact effect of microgravity and the subsequent fluid shifts and muscle mass loss on these parameters. Unfortunately, not all responses to actual microgravity can be reproduced with head-down tilt bed rest studies, which complicates research on Earth. Better understanding of the effects of microgravity on kidney function, volume regulation and osmoregulation are needed with the advent of long-term deep space missions and planetary surface explorations during which orthostatic intolerance complaints or kidney stone formation can be life-threatening for astronauts. Galactic cosmic radiation may be a new threat to kidney function. In this review, we summarise and highlight the current understandings of the effects of microgravity on kidney function, volume regulation and osmoregulation and discuss knowledge gaps that future studies should address. [ABSTRACT FROM AUTHOR]

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Hypotonicity-induced cell swelling is characterized by a modification in cell architecture associated with actin cytoskeleton remodeling. The ezrin/radixin/moesin (ERM) family proteins are important signal transducers during actin reorganization regulated by the monomeric G proteins of the Rho family. We report here that in collecting duct CD8 cells hypotonicity-induced cell swelling resulted in deep actin reorganization, consisting of loss of stress fibers and formation of F-actin patches in membrane protrusions where the ERM protein moesin was recruited. Cell swelling increased the interaction between actin and moesin and induced the transition of moesin from an oligomeric to a monomeric functional conformation, characterized by both the COOH- and N[H.sub.2]-terminal domains being exposed. In this conformation, which is stabilized by phosphorylation of a conserved threonine in the COOH-terminal domain by PKC or Rho kinase, moesin can bind interacting proteins. Interestingly, hypotonic stress increased the amount of threoninephosphorylated moesin, which was prevented by the PKC-[alpha] inhibitor Go-6976 (50 nM). In contrast, the Rho kinase inhibitor Y-27632 (1 [micro]M) did not affect the hypotonicity-induced increase in phosphorylated moesin. The present data represent the first evidence that hypotonicity-induced actin remodeling is associated with phosphorylated moesin recruitment at the cell border and interaction with actin. ezrin/radixin/moesin; protein kinase C; Rho

Aquaporin-2 (AQP2), when expressed in fully differentiated 3T3-L1 adipocytes, displays cAMP-dependent plasma membrane translocation in a manner similar to its behavior in renal epithelial cells. The translocation of AQP2 required phosphorylation at serine 256, as the expression of AQP2/S256D was constitutively plasma membrane localized, whereas AQP2/S256A was refractory to forskolin stimulation. Unlike GLUT4, this property is not inhibited by depolymerization of cortical actin. In addition, coexpression with the dominant negative form of TC10 (TC10/T31N) or inhibition of phosphatidylinositol 3-kinase did not abrogate the cAMP-mediated response. Under basal conditions, AQP2 is localized in both the perinuclear region and in punctate vesicles scattered within the periphery of the cell. Two- and three-dimensional confocal immunofluorescence microscopy demonstrated that the adipocyte AQP2 cAMP-responsive compartment was distinct from the GLUT4 insulin-responsive compartment. Consistent with this conclusion, insulin was an effective stimulator of GLUT4 translocation but had no effect on AQP2. Conversely, forskolin induced AQP2 translocation but not GLUT4. Colocalization studies with the early endosomal marker EEA1 and transferrin receptor suggested that the AQP2 compartment is mostly distinct from endosomal vesicles. Interestingly. however, the peripheral AQP2 vesicles significantly overlapped vesicle-associated membrane protein-2, underscoring the role of the latter in hormone-regulated exocytosis. To acquire insulin responsiveness following biosynthesis, GLUT4 undergoes a slow sorting step that requires 6-9 h. In contrast, AQP2 rapidly acquires forskolin responsiveness (3 h following biosynthesis) and directly enters the cAMP-regulated compartment without transiting the plasma membrane. Together, these data demonstrate that adipocytes display two different intracellular sorting mechanisms that direct distinct hormone-sensitive partitioning of GLUT4 and AQP2. hormone-regulated exocytosis; trans-Golgi network: renal epithelial cells

The one-dimensional propagation of magnetic domain walls in an isotropic, linearly elastic, magnetostrictive material is investigated in the framework of the extended Landau-Lifshitz-Gilbert equation where the effects of a spin-polarized current and a rate-independent dry-friction dissipation are taken into account. In our analysis, it is assumed that the ferromagnet is subject to a spatially uniform biaxial in-plain stress generated by a piezoelectric substrate combined with the former in a multiferroic heterostructure. Moreover, a possible connection between the dry-friction mechanism and the piezo-induced strains is conjectured. By adopting the traveling waves ansatz, the effect of such a stress on the domain wall dynamics is explored in both steady and precessional regimes. In particular, it is proved that the magnetoelastic contribution, while it does not formally modify the classical solution, affects both the propagation threshold and the Walker Breakdown conditions involved in the steady regime, in agreement with recent experimental results. In the precessional regime, it is shown that the existence of a correlation between the piezo-induced strains and dry-friction leads to an upward shift of the domain wall velocity. [ABSTRACT FROM AUTHOR]

Exposure to actual or simulated microgravity results in alterations of renal function, fluid redistribution, and bone loss, which is coupled to a rise of urinary calcium excretion. We provided evidence that high calcium delivery to the collecting duct reduces local Aquaporin 2 (AQP2)-mediated water reabsorption under vasopressin action, thus limiting the maximal urinary concentration to reduce calcium saturation. To investigate early renal adaptation into simulated microgravity, we investigated the effects of 10 days of strict bedrest in 10 healthy volunteers. We report here that 10 days of inactivity are associated with a transient, significant decrease (day 5) in vasopressin (copeptin) paralleled by a decrease in AQP2 excretion, consistent with an increased central volume to the heart, resulting in reduced water reabsorption. Moreover, bedrest caused a significant increase in calciuria secondary to bone demineralization paralleled by a decrease in PTH. Urinary osteopontin, a glycoprotein exerting a protective effect on stone formation, was significantly reduced during bedrest. Moreover, a significant increase in adrenomedullin (day 5), a peptide with vasodepressor properties, was observed at day 5, which may contribute to the known reduced orthostatic capacity post-bedrest. We conclude that renal function is altered in simulated microgravity and is associated with an early increase in the risk of stone formation and reduced orthostatic capacity post-bedrest within a few days of inactivity. [ABSTRACT FROM AUTHOR]

In this study, we analyzed the effect of a therapeutic intervention in 46 enuretic children, 26 (57%) of whom were hypercalciuric. All the patients (n = 46) were treated with DDAVP for 3-6 mo. The hypercalciuric patients (n = 26) received a low-calcium diet (~500 mg/day) for the same period. After the therapy, the bed-wetting episodes stopped in 80% of the 46 patients tested. In those patients having low-AVP levels before the therapy, circulating AVP concentration returned to normal (>4 pg/ml), and the hypercalciuria was resolved in the hypercalciuric patients (calcium/creatinine ratio aquaporin; hypercalciuria; enuresis; calcium-sensing receptors; vasopressin

Tamma, Grazia, Enno Klussmann, Kenan Maric, Klaus Aktories, Maria Svelto, Walter Rosenthal, and Giovanna Valenti. Rho inhibits cAMP-induced translocation of aquaporin-2 into the apical membrane of renal cells. Am J Physiol Renal Physiol 281: F1092-F1101, 2001. First published August 8, 2001; 10.1152/ajprenal.00091.2001.--We have recently demonstrated that actin depolymerization is a prerequisite for cAMP-dependent translocation of the water channel aquaporin-2 (AQP2) into the apical membrane in AQP2-transfected renal CD8 cells (29). The Rho family of small GTPases, including Cdc42, Rac, and Rho, regulates the actin cytoskeleton. In AQP2-transfected CD8 cells, inhibition of Rho GTPases with Clostridium difficile toxin B or with C. limosum C3 fusion toxin, as well as incubation with the Rho kinase inhibitor, Y-27632, caused actin depolymerization and translocation of AQP2 in the absence of the cAMP-elevating agent forskolin. Both forskolin and C3 fusion toxin-induced AQP2 translocation were associated with a similar increase in the osmotic water permeability coefficient. Expression of constitutively active RhoA induced formation of stress fibers and abolished AQP2 translocation in response to forskolin. Cytochalasin D induced both depolymerization of F-actin and AQP2 translocation, suggesting that depolymerization of F-actin is sufficient to induce AQP2 translocation. Together, these data indicate that Rho inhibits cAMP-dependent translocation of AQP2 into the apical membrane of renal principal cells by controlling the organization of the actin cytoskeleton. aquaporin; C3 toxin; toxin B; actin cytoskeleton; G proteins; adenosine 3',5'-cyclic monophosphate Received 16 March 2001; accepted in final form 6 August 2001

Generation of polyclonal antibodies, immunofluorescence and immunoelectron microscopies, and immunoprecipitation reveal the presence of a aquaporin/MIP26 family-related protein, the basolateral integral membrane protein (BLIP), in the basolateral membrane of collecting duct principal cells. BLIP serum identifies CHIP28 and MIP26 on Western blotting and stains only the MIP26 in lens fibers. The basolateral membrane of parietal cells is also stained by BLIP serum.

The main features of the spin-waves excited at the threshold via spin-polarized currents in a one-dimensional normally-to-plane magnetized waveguide are quantitatively determined both analytically and numerically. In particular, the dependence of the threshold current, frequency, wavenumber, and decay length is investigated as a function of the size of the nanocontact area through which the electric current is injected. From the analytical viewpoint, such a goal has required to solve the linearized Landau-Lifshitz-Gilbert-Slonczewski equation together with boundary and matching conditions associated with the waveguide geometry. Owing to the complexity of the resulting transcendent system, particular solutions have been obtained in the cases of elongated and contracted nanocontacts. These results have been successfully compared with those arising from numerical integration of the abovementioned transcendent system and with micromagnetic simulations. This quantitative agreement has been achieved thanks to the model here considered which takes explicitly into account the diagonal demagnetizing factors of a rectangular prism as well as the dependence of the relaxation rate on the wavenumber. Our analysis confirmed that the spinwave features supported by such a waveguide geometry are significantly different from the ones observed in classical two-dimensional nanocontact devices. Moreover, it has been proved that the characteristic parameters depend strongly on the material properties and on the modulus of external field, but they could be independent of the nanocontact length. Finally, it is shown that spintransfer oscillators based on contracted nanocontacts have a better capability to transmit spinwaves over large distances. [ABSTRACT FROM AUTHOR]

In the last few years, the production of olive oil has incredibly increased due to its beneficial properties on human health. On the other hand, the amount of waste and by-products derived from the olive oil industry has increased as well, prompting the development of new fields of research aiming to reduce disposal costs and valorize bioactive compounds from the viewpoint of the green economy. Interestingly, olive oil and by-products contain numerous molecules, including phenols, exhibiting pleiotropic effects in both in vitro and in vivo studies. This review aims to describe the more recent studies focusing to identify and describe the potential roles and the new applications of extracts isolated from wastes and by-products or specific compounds, such as hydroxytyrosol (HT) and oleuropein. Extracts or bioactive molecules from olive oil and by-products have been proposed as a food additive, to produce biofuel, for animal feeding, and to create new matrices in bioremediation protocols. Moreover, bio-compounds have been described to have numerous beneficial effects on human health as they reduce the risk of developing certain chronic diseases. Despite the already published studies, more research is necessary to valorize bioactive compounds in olive oil and by-products, as well as their potential use to improve human health and green applications in different industrial processes. [ABSTRACT FROM AUTHOR]

The formation of Turing vegetation patterns in flat arid environments is investigated in the framework of a generalized version of the hyperbolic Klausmeier model. The extensions here considered involve, on the one hand, the strength of the rate at which rainfall water enters into the soil and, on the other hand, the functional dependence of the inertial times on vegetation biomass and soil water. The study aims at elucidating how the inclusion of these generalized quantities affects the onset of bifurcation of supercritical Turing patterns as well as the transient dynamics observed from an uniformly vegetated state towards a patterned state. To achieve these goals, linear and multiple‐scales weakly nonlinear stability analysis are addressed, this latter being inspected in both large and small spatial domains. Analytical results are then corroborated by numerical simulations, which also serve to describe more deeply the spatio‐temporal evolution of the emerging patterns as well as to characterize the different timescales involved in vegetation dynamics. [ABSTRACT FROM AUTHOR]

A systematic representation of the fourth-order magnetostriction tensor for all crystal classes is presented, based on the formalism proposed by Walpole (Proc R Soc Lond Ser A 1984; 391: 149–179). This representation allows the general, unconstrained case, as well as the case in which the magnetostrictive strain is assumed to be isochoric, to be studied. The knowledge of the fourth-order magnetostriction tensor enables the stress-free magnetostrictive strain tensor as well as the scalar strain in a given direction to be calculated. [ABSTRACT FROM AUTHOR]

The effects of secondary seed dispersal on the dynamics of banded vegetation are investigated in the framework of a generalized version of one of the easiest tools for the description of pattern formation along the hillsides of semi-arid environments: the Klausmeier model. The generalization here considered consists in augmenting the evolution equation for the vegetation biomass with an advection term mimicking the anisotropic dispersal of seeds by overland flow. Linear stability analysis is used to deduce the threshold condition for the occurrence of wave instability as well as to obtain approximated explicit expressions for some key quantities: pattern speed, locus of stationary patterns and excited wavenumber. The generalized model is also integrated numerically considering two different sets of initial conditions that yield pattern dynamics originating from degradation of uniform vegetation or colonization of bare ground. These numerical simulations are performed to corroborate the analytical predictions, to characterize more deeply the propagating character of the edges of vegetation patches and to emphasize how distinct initial conditions may lead to significantly different ecological scenarios. [ABSTRACT FROM AUTHOR]

Cadmium (Cd) is a heavy and highly toxic metal that contaminates air, food and water. Cadmium accumulates in several organs altering normal functions. The kidney is the major organ at risk of damage from chronic exposure to cadmium as a contaminant in food and water. This study aims to investigate the beneficial effects of OLE in renal collecting duct MCD4 cells exposed to a low dose cadmium (1 μM). In MCD4 cells cadmium caused an increase in ROS production, as well as generation of lipid droplets and reduced cell viability. Moreover, cadmium exposure led to a remarkable increase in the frequency of micronuclei and DNA double-strand breaks, assessed using the alkaline comet assay. In addition, cadmium dramatically altered cell cytoskeleton architecture and caused S-glutathionylation of actin. Notably, all cadmium-induced cellular deregulations were prevented by co-treatment with OLE, possibly due to its antioxidant action and to the presence of bioactive phytocompounds. Indeed, OLE treatment attenuated Cd-induced actin S-glutathionylation, thereby stabilizing actin filaments. Taken together, these observations provide a novel insight into the biological action of OLE in renal cells and support the notion that OLE may serve as a potential adjuvant against cadmium-induced nephrotoxicity. [ABSTRACT FROM AUTHOR]