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Ascending urinary tract infection (UTI) and pyelonephritis caused by uropathogenic Escherichia coli (UPEC) are very common infections that can cause severe kidney damage. Collecting duct cells, the site of hormonally regulated ion transport and water absorption controlled by vasopressin, are the preferential intrarenal site of bacterial adhesion and initiation of inflammatory response. We investigated the effect of the potent V2 receptor (V2R) agonist deamino-8-D-arginine vasopressin (dDAVP) on the activation of the innate immune response using established and primary cultured collecting duct cells and an experimental model of ascending UTI. dDAVP inhibited Toll-like receptor 4-mediated nuclear factor kappaB activation and chemokine secretion in a V2R-specific manner. The dDAVP-mediated suppression involved activation of protein phosphatase 2A and required an intact cystic fibrosis transmembrane conductance regulator Cl- channel. In vivo infusion of dDAVP induced a marked fall in proinflammatory mediators and neutrophil recruitment, and a dramatic rise in the renal bacterial burden in mice inoculated with UPECs. Conversely, administration of the V2R antagonist SR121463B to UPEC-infected mice stimulated both the local innate response and the antibacterial host defense. These findings evidenced a novel hormonal regulation of innate immune cellular activation and demonstrate that dDAVP is a potent modulator of microbial-induced inflammation in the kidney.
In the present study, adrenocorticotropic hormone (ACTH) release and intracellular calcium ([Ca(2+)](i)) increase induced by arginine vasopressin (AVP) were characterized in collagenase-dispersed and 3-day cultured rat anterior pituitary cells. AVP and the selective vasopressin V(1b) receptor agonist, [1-deamino-4-cyclohexylalanine]AVP (d[Cha(4)]AVP) induced ACTH release with nanomolar potencies in both cell preparations, and produced a maximal stimulation that was about 1.5 fold greater in the 3-day cultured cells, indicating that the vasopressin V(1b) receptor-ACTH release pathway is enhanced over time in culture. In dispersed cells, AVP, oxytocin and d[Cha(4)]AVP induced [Ca(2+)](i) increases with nanomolar potencies. The selective vasopressin V(1a) receptors antagonist, SR49059 (100 nM), together with the selective oxytocin receptors antagonist (d(CH(2))(5)(1)Tyr(Me)(2),Thr(4),Orn(8),Tyr-NH(2)(9)-vasotocin (100 nM), inhibited the maximal AVP response by ~70%, without affecting the response to d[Cha(4)]AVP, suggesting that the V(1b) receptor was only partially responsible for the AVP-induced [Ca(2+)](i) increase. In contrast, in 3-day cultures, AVP induced an increase in [Ca(2+)](i), while oxytocin and d[Cha(4)]AVP did not. The response to AVP was completely antagonized by SR49059, whereas the vasopressin V(1b) receptor antagonists, SSR149415 and (d(CH(2))(5)(1)Tyr(Me)(2),Thr(4),Orn(8),Tyr-NH(2)(9))-vasotocin had no effect, indicating that the [Ca(2+)](i) increase was mediated exclusively by vasopressin V(1a) receptors. In conclusion, the enhancement of vasopressin V(1b) receptor-mediated ACTH release and the lack of a detectable vasopressin V(1b) receptor coupling to [Ca(2+)](i) increase in cultured cells suggests the activation of a different/additional signaling pathway in the molecular mechanism of ACTH release.
The acute effect of endothelin-1 (ET-1) on the hypothalamo-pituitary-adrenal (HPA) axis has been investigated in the rat. The plasma concentrations of arginine-vasopressin (AVP), ACTH, aldosterone and corticosterone have been measured by RIA 30 and 60 min after ET-1 administration. ET-1 (2.0 nmol kg(-1) raised AVP plasma concentration at both 30 and 60 min. ET-1 did not alter the ACTH plasma level at 30 min, but markedly increased it at 60 min. ACTH response was unaffected by the simultaneous administration of AVP-receptor antagonists (AVP-As) Des-Gly-[Phaa1,D-Tyr(Et)2,Lys6,Arg8]-vasopressin or [Deamino-Pen1,Tyr(Me)2,Arg8]-vasopressin (20 nmol kg(-1), but abolished by the corticotropin-releasing hormone (CRH)-receptor antagonist alpha-helical-CRH(9-41) (alpha-CRH, 10 nmol kg(-1). ET-1 evoked significant rises in the blood levels of aldosterone and corticosterone at both 30 and 60 min. AVP-As abrogated the response at 30 min, while alpha-CRH was ineffective. Both AVP-As and alpha-CRH partially reversed adrenocortical secretory response at 60 min. Collectively, these findings confirm that systemically administered ET-1 stimulates rat HPA axis, and provide evidence that the mechanism underlying this effect may involve the sequential activation of AVP and CRH release.
Vasopressin-synthesizing neurons are located in several brain regions, including the hypothalamic paraventricular nucleus (PVN), supraoptic nucleus (SON) and suprachiasmatic nucleus (SCN). Vasopressin has been shown to have various functions in the brain, including social recognition memory, stress responses, emotional behaviors and circadian rhythms. The precise physiological functions of vasopressin-synthesizing neurons in specific brain regions remain to be clarified. Conditional ablation of local vasopressin-synthesizing neurons may be a useful tool for investigation of the functions of vasopressin neurons in the regions. In the present study, we characterized a transgenic rat line that expresses a mutated human diphtheria toxin receptor under control of the vasopressin gene promoter. Under a condition of salt loading, which activates the vasopressin gene in the hypothalamic PVN and SON, transgenic rats were i.c.v. injected with diphtheria toxin. Intracerebroventricular administration of diphtheria toxin after salt loading depleted vasopressin-immunoreactive cells in the hypothalamic PVN and SON, but not in the SCN. The number of oxytocin-immunoreactive cells in the hypothalamus was not significantly changed. The rats that received i.c.v. diphtheria toxin after salt loading showed polydipsia and polyuria, which were rescued by peripheral administration of 1-deamino-8-d-arginine vasopressin via an osmotic mini-pump. Intrahypothalamic administration of diphtheria toxin in transgenic rats under a normal hydration condition reduced the number of vasopressin-immunoreactive neurons, but not the number of oxytocin-immunoreactive neurons. The transgenic rat model can be used for selective ablation of vasopressin-synthesizing neurons and may be useful for clarifying roles of vasopressin neurons at least in the hypothalamic PVN and SON in the rat.
Three subtypes of human (h) arginine vasopressin (AVP) receptors, hV1A, hV1B and hV2, were stably expressed in Chinese hamster ovary (CHO) cells and characterized by [3H]-AVP binding studies. In addition, the coupling of the expressed receptor protein to a variety of signal transduction pathways was investigated. Scatchard analysis of saturation isotherms for the specific binding of [3H]-AVP to membranes, prepared from CHO cells transfected with hV1A, hV1B and hV2 receptors, yielded an apparent equilibrium dissociation constant (Kd) of 0.39, 0.25 and 1.21 nM and a maximum receptor density (Bmax) of 1580 fmol mg(-1) protein, 5230 fmol mg(-1) protein and 7020 fmol mg(-1) protein, respectively. Hill coefficients did not differ significantly from unity, suggesting binding to homogenous, non-interacting receptor populations. Pharmacological characterization of the transfected human AVP receptors was undertaken by measuring the relative ability of nonpeptide AVP receptor antagonists, YM087, OPC-21268, OPC-31260, SR 49059 and SR 121463A, to inhibit binding of [3H]-AVP. At hV1A receptors, the relative order of potency was SR49059>YM087>OPC-31260>SR 121463A> >OPC-21268 and at hV2 receptors, YM087=SR 121463A>OPC-31260>SR 49059> >OPC-21268. In contrast, the relative order of potency, at hV1B receptors, was SR 49059> >SR 121463A=YM087=OPC-31260=OPC-21268. In CHO cells expressing either hV1A or hV1B receptors, AVP caused a concentration-dependent increase in intracellular Ca2+ concentration ([Ca2+]i) with an EC50 value of 1.13 nM and 0.90 nM, respectively. In contrast, stimulation of CHO cells expressing hV2 receptors resulted in an accumulation of cyclic AMP with an EC50 value of 2.22 nM. The potency order of antagonists in inhibiting AVP-induced [Ca2+]i or cyclic AMP response was similar to that observed in radioligand binding assays. In conclusion, we have characterized the pharmacology of human cloned V1A, V1B and V2 receptors and used these to determine the affinity, selectivity and potency of nonpeptide AVP receptor antagonists. Thus they may prove to be a valuable tool in further examination of the physiological and pathophysiological roles of AVP.
Colorectal cancer (CRC) is a leading cause of cancer-associated mortality worldwide. Despite being an essential component of systemic chemotherapy for advanced CRC, 5-fluorouracil (5-FU) clinical use has severe limitations, such as high toxicity, low selectivity and drug resistance. [V4Q5]dDAVP (1-deamino-4-valine-5-glutamine-8-D-arginine vasopressin) is a peptide vasopressin analog and a selective agonist of the arginine vasopressin type 2 membrane receptor (AVPR2), expressed in microvascular and tumor tissue. This synthetic compound has well-proven antitumor and antimetastatic activity in different tumor types, including metastatic CRC. The objective of this work was to assess the potential combinational benefits in preclinical CRC models after [V4Q5]dDAVP addition to 5-FU.
Vasopressin is an efficient remedy for septic shock patients as its great capacity in promoting hemodynamic stabilization. The aim of current systematic review and meta-analysis is to compare the clinical efficiency of vasopressin or its analogs with sole catecholamines on patients with septic shock.
Corticotropin-inhibiting peptide (CIP), the 7-38 fragment of human ACTH(1-39), is known to act as an antagonist of ACTH receptors. Accordingly, CIP has been found to inhibit ACTH-stimulated glucocorticoid secretion of dispersed rat adrenocortical cells, without per se affecting the basal production. We confirmed these findings, but unexpectedly observed that CIP concentration-dependently raised basal aldosterone secretion from fresh suspensions of rat zona glomerulosa (ZG) cells, maximal effective concentration being 10(-6) M. CIP (10(-6) M) partially reversed the ZG-cell response to ACTH, but not to the Ca2+-dependent agonists angiotensin-II (ANG-II) and K+. The aspecific ANG-II-receptor antagonist saralasin (10(-6) M) blocked the aldosterone response of ZG cells to 10(-6) M CIP, and in the presence of the Ca2+-channel blocker verapamil CIP was ineffective. Collectively, these findings suggest that CIP enhances aldosterone secretion of rat ZG through a mechanism involving the activation of ANG-II receptors and the consequent rise in the cytosolic Ca2+ concentration. They also stress that this side-effect of CIP must be taken into account in interpreting the results of investigations on the adrenal cortex, where CIP has been employed as an ACTH-receptor antagonist.
The half-life and mean residence time (MRT) of infused recombinant factor VIII (FVIII) concentrate are associated with pre-infusion levels of von Willebrand factor (VWF) in severely affected hemophilia A patients. It is currently unknown if individual FVIII concentrate half-life and MRT can be extended by increasing endogenous VWF levels. Aim: Our aim was to evaluate the effect of a 1-deamino-8-D-arginine vasopressin (DDAVP)-induced rise in VWF concentration on the pharmacokinetics of infused FVIII in hemophilia A patients.
Chronic visceral hypersensitivity (CVH) is a major pathophysiological feature of patients experiencing in irritable bowel syndrome (IBS) and other disorders with visceral pain. However, little is known about its regulation of the central nucleus. In this research, we investigated the protective effect of microinjection of glutamate into hypothalamus paraventricular nucleus (PVN) on CVH and its possible regulatory mechanism in rats. Visceral sensitivity was assessed by pain threshold, abdominal withdrawal reflex (AWR) score, and the abdominal external oblique muscle electromyography (EMG) amplitude. Pathological changes in colorectal mucosa were assessed using immunohistochemical, biochemical analysis and Western blot. Results showed that microinjection of different doses of glutamate into PVN reduced the visceral sensitivity in a dose-dependent manner. This effect can be reversed after chemical ablation of PVN or nucleus tractus solitarius (NTS) or pretreatment with the arginine vasopressin (AVP)-V1 receptor antagonist ([Deamino-pen1,val4,D-Arg8]-vasopressin) DPVDAV into NTS. The vagus discharge frequency was significantly reduced after the glutamate microinjection into PVN. Additionally, oxidation, proliferation and apoptosis in colorectal mucosa were related to the CVH regulations. These findings suggested that PVN and NTS are involved in the regulatory process of CVH and exert the protective effect on CVH, providing new ideas and therapeutic targets for CVH research.
Anticholinergics, therapeutic agents for overactive bladder, are clinically suggested to reduce urine output. We investigated whether this effect is due to bladder or kidney urine reabsorption. Various solutions were injected into the bladder of urethane-anesthetized SD rats. The absorption rate for 2 h was examined following the intravenous administration of the anticholinergics imidafenacin (IM), atropine (AT), and tolterodine (TO). The bilateral ureter was then canulated and saline was administered to obtain a diuretic state. Anticholinergics or 1-deamino-[8-D-arginine]-vasopressin (dDAVP) were intravenously administered. After the IM and dDAVP administrations, the rat kidneys were immunostained with AQP2 antibody, and intracellular cAMP was measured. The absorption rate was ~ 10% of the saline injected into the bladder and constant even when anticholinergics were administered. The renal urine among peaked 2 h after the saline administration. Each of the anticholinergics significantly suppressed the urine production in a dose-dependent manner, as did dDAVP. IM and dDAVP increased the intracellular cAMP levels and caused the AQP2 molecule to localize to the collecting duct cells' luminal side. The urinary reabsorption mechanism through the bladder epithelium was not activated by anticholinergic administration. Thus, anticholinergics suppress urine production via an increase in urine reabsorption in the kidneys' collecting duct cells via AQP2.
During postnatal development rats demonstrate an age-dependent increase in NaCl chorda tympani (CT) responses and the number of functional apical amiloride-sensitive epithelial Na+ channels (ENaCs) in salt sensing fungiform (FF) taste receptor cells (TRCs). Currently, the intracellular signals that regulate the postnatal development of salt taste have not been identified. We investigated the effect of cAMP, a downstream signal for arginine vasopressin (AVP) action, on the postnatal development of NaCl responses in 19-23 day old rats. ENaC-dependent NaCl CT responses were monitored after lingual application of 8-chlorophenylthio-cAMP (8-CPT-cAMP) under open-circuit conditions and under ±60 mV lingual voltage clamp. Behavioral responses were tested using 2 bottle/24h NaCl preference tests. The effect of [deamino-Cys1, D-Arg8]-vasopressin (dDAVP, a specific V2R agonist) was investigated on ENaC subunit trafficking in rat FF TRCs and on cAMP generation in cultured adult human FF taste cells (HBO cells). Our results show that in 19-23 day old rats, the ENaC-dependent maximum NaCl CT response was a saturating sigmoidal function of 8-CPT-cAMP concentration. 8-CPT-cAMP increased the voltage-sensitivity of the NaCl CT response and the apical Na+ response conductance. Intravenous injections of dDAVP increased ENaC expression and γ-ENaC trafficking from cytosolic compartment to the apical compartment in rat FF TRCs. In HBO cells dDAVP increased intracellular cAMP and cAMP increased trafficking of γ- and δ-ENaC from cytosolic compartment to the apical compartment 10 min post-cAMP treatment. Control 19-23 day old rats were indifferent to NaCl, but showed clear preference for appetitive NaCl concentrations after 8-CPT-cAMP treatment. Relative to adult rats, 14 day old rats demonstrated significantly less V2R antibody binding in circumvallate TRCs. We conclude that an age-dependent increase in V2R expression produces an AVP-induced incremental increase in cAMP that modulates the postnatal increase in TRC ENaC and the neural and behavioral responses to NaCl.
Sorting nexin 27 (SNX27), a PDZ (Postsynaptic density-95/Discs large/Zonula occludens 1) domain-containing protein, cooperates with a retromer complex, which regulates intracellular trafficking and the abundance of membrane proteins. Since the carboxyl terminus of aquaporin-2 (AQP2c) has a class I PDZ-interacting motif (X-T/S-X-Φ), the role of SNX27 in the regulation of AQP2 was studied. Co-immunoprecipitation assay of the rat kidney demonstrated an interaction of SNX27 with AQP2. Glutathione S-transferase (GST) pull-down assays revealed an interaction of the PDZ domain of SNX27 with AQP2c. Immunocytochemistry of HeLa cells co-transfected with FLAG-SNX27 and hemagglutinin (HA)-AQP2 also revealed co-localization throughout the cytoplasm. When the PDZ domain was deleted, punctate HA-AQP2 labeling was localized in the perinuclear region. The labeling was intensively overlaid by Lysotracker staining but not by GM130 labeling, a cis-Golgi marker. In rat kidneys and primary cultured inner medullary collecting duct cells, the subcellular redistribution of SNX27 was similar to AQP2 under 1-deamino-8-D-arginine vasopressin (dDAVP) stimulation/withdrawal. Cell surface biotinylation assay showed that dDAVP-induced AQP2 translocation to the apical plasma membrane was unaffected after SNX27 knockdown in mpkCCD cells. In contrast, the dDAVP-induced AQP2 protein abundance was significantly attenuated without changes in AQP2 mRNA expression. Moreover, the AQP2 protein abundance was markedly declined during the dDAVP withdrawal period after stimulation under SNX27 knockdown, which was inhibited by lysosome inhibitors. Autophagy was induced after SNX27 knockdown in mpkCCD cells. Lithium-induced nephrogenic diabetes insipidus in rats revealed a significant downregulation of SNX27 in the kidney inner medulla. Taken together, the PDZ domain-containing SNX27 interacts with AQP2 and depletion of SNX27 contributes to the autophagy-lysosomal degradation of AQP2.
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