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International Journal of Molecular... Sep 2023Autosomal-Dominant Polycystic Kidney Disease (ADPKD) is a monogenic disorder initiated by mutations in either or genes, responsible for encoding polycystin 1 and... (Review)
Review
Autosomal-Dominant Polycystic Kidney Disease (ADPKD) is a monogenic disorder initiated by mutations in either or genes, responsible for encoding polycystin 1 and polycystin 2, respectively. These proteins are primarily located within the primary cilia. The disease follows an inexorable progression, leading most patients to severe renal failure around the age of 50, and extra-renal complications are frequent. A cure for ADPKD remains elusive, but some measures can be employed to manage symptoms and slow cyst growth. Tolvaptan, a vasopressin V2 receptor antagonist, is the only drug that has been proven to attenuate ADPKD progression. Recently, autophagy, a cellular recycling system that facilitates the breakdown and reuse of aged or damaged cellular components, has emerged as a potential contributor to the pathogenesis of ADPKD. However, the precise role of autophagy in ADPKD remains a subject of investigation, displaying a potentially twofold impact. On the one hand, impaired autophagy may promote cyst formation by inducing apoptosis, while on the other hand, excessive autophagy may lead to fibrosis through epithelial to mesenchymal transition. Promising results of autophagy inducers have been observed in preclinical studies. Clinical trials are warranted to thoroughly assess the long-term safety and efficacy of a combination of autophagy inducers with metabolic and/or aquaferetic drugs. This research aims to shed light on the complex involvement of autophagy in ADPKD, explore the regulation of autophagy in disease progression, and highlight the potential of combination therapies as a promising avenue for future investigations.
Topics: Humans; Aged; Polycystic Kidney, Autosomal Dominant; Epithelial-Mesenchymal Transition; Kidney; Autophagy; Cysts
PubMed: 37834113
DOI: 10.3390/ijms241914666 -
Cureus Sep 2023Vasodilatory shock can be caused by septic shock, neurogenic shock, anaphylaxis, drugs, and toxins. Vasopressin is commonly used for the restoration of vasomotor tone in...
Vasodilatory shock can be caused by septic shock, neurogenic shock, anaphylaxis, drugs, and toxins. Vasopressin is commonly used for the restoration of vasomotor tone in vasodilatory shock due to sepsis. This agent exerts its vasoconstrictive effect via smooth muscle V1 receptors and has antidiuretic activity via kidney V2 receptors. Stimulation of V2 receptors results in the integration of aquaporin 2 channels into the apical membrane of collecting ducts leading to free water reabsorption. This antidiuretic action of vasopressin predisposes to hyponatremia. Yet, the development of hyponatremia with the use of vasopressin in critically ill patients with sepsis is rare. A 75-year-old female presented after a suicidal attempt by ingestion of amlodipine and lisinopril. Despite adequate intravenous fluids administration, she remained hypotensive, requiring the initiation of vasopressors. She developed hyponatremia after initiation of vasopressin due to the absence of endotoxemia, and her serum sodium normalized once vasopressin was discontinued. We recommend monitoring for hyponatremia as a complication of vasopressin, especially in patients without sepsis.
PubMed: 37829951
DOI: 10.7759/cureus.45053 -
Nephrology, Dialysis, Transplantation :... Mar 2024The only treatment proven to be renoprotective in autosomal dominant polycystic kidney disease (ADPKD) is a vasopressin V2-receptor antagonist (V2RA). However,... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
The only treatment proven to be renoprotective in autosomal dominant polycystic kidney disease (ADPKD) is a vasopressin V2-receptor antagonist (V2RA). However, aquaresis-associated side effects limit tolerability. We investigated whether salt and/or protein intake influences urine volume and related endpoints in V2RA-treated ADPKD patients.
METHODS
In this randomized, controlled, double-blind, crossover trial, ADPKD patients treated with maximally tolerated dose of a V2RA were included. While on a low salt and low protein diet, patients were given additional salt and protein to mimic regular intake, which was subsequently replaced by placebo in random order during four 2-week periods. Primary endpoint was change in 24-h urine volume. Secondary endpoints were change in quality of life, measured glomerular filtration rate (mGFR), blood pressure and copeptin level.
RESULTS
Twelve patients (49 ± 8 years, 25.0% male) were included. Baseline salt and protein intake were 10.8 ± 1.3 g/24-h and 1.2 ± 0.2 g/kg/24-h, respectively. During the low salt and low protein treatment periods, intake decreased to 5.8 ± 1.6 g/24-h and 0.8 ± 0.1 g/kg/24-h, respectively. Baseline 24-h urine volume (5.9 ± 1.2 L) decreased to 5.2 ± 1.1 L (-11%, P = .004) on low salt and low protein, and to 5.4 ± 0.9 L (-8%, P = .04) on low salt. Reduction in 24-h urine volume was two times greater in patients with lower urine osmolality (-16% vs -7%). Polyuria quality of life scores improved in concordance with changes in urine volume. mGFR decreased during the low salt and low protein, while mean arterial pressure did not change during study periods. Plasma copeptin decreased significantly during low salt and low protein periods.
CONCLUSION
Lowering dietary salt and protein intake has a minor effect on urine volume in V2RA-treated ADPKD patients. Reduced intake of osmoles decreased copeptin concentrations and might thus increase the renoprotective effect of a V2RA in ADPKD patients.
Topics: Female; Humans; Male; Antidiuretic Hormone Receptor Antagonists; Glomerular Filtration Rate; Kidney; Polycystic Kidney, Autosomal Dominant; Polyuria; Quality of Life; Sodium Chloride, Dietary; Tolvaptan; Double-Blind Method; Cross-Over Studies
PubMed: 37804179
DOI: 10.1093/ndt/gfad218 -
Frontiers in Endocrinology 2023The diabetic kidney disease (DKD) is the major cause of the chronic kidney disease (CKD). Enhanced plasma vasopressin (VP) levels have been associated with the... (Review)
Review
The diabetic kidney disease (DKD) is the major cause of the chronic kidney disease (CKD). Enhanced plasma vasopressin (VP) levels have been associated with the pathophysiology of DKD and CKD. Stimulation of VP release in DKD is caused by glucose-dependent reset of the osmostat leading to secondary pathophysiologic effects mediated by distinct VP receptor types. VP is a stress hormone exhibiting the antidiuretic action in the kidney along with broad adaptive effects in other organs. Excessive activation of the vasopressin type 2 (V2) receptor in the kidney leads to glomerular hyperfiltration and nephron loss, whereas stimulation of vasopressin V1a or V1b receptors in the liver, pancreas, and adrenal glands promotes catabolic metabolism for energy mobilization, enhancing glucose production and aggravating DKD. Increasing availability of selective VP receptor antagonists opens new therapeutic windows separating the renal and extra-renal VP effects for the concrete applications. Improved understanding of these paradigms is mandatory for further drug design and translational implementation. The present concise review focuses on metabolic effects of VP affecting DKD pathophysiology.
Topics: Humans; Diabetic Nephropathies; Vasopressins; Receptors, Vasopressin; Renal Insufficiency, Chronic; Glucose; Diabetes Mellitus
PubMed: 37790608
DOI: 10.3389/fendo.2023.1176199 -
International Journal of Molecular... Sep 2023Vasopressin/oxytocin (VP/OT)-type neuropeptide is an ancient neurophysin-associated neuropeptide and has been intensively studied to be involved in multiple...
Vasopressin/oxytocin (VP/OT)-type neuropeptide is an ancient neurophysin-associated neuropeptide and has been intensively studied to be involved in multiple physiological processes in protostomian and deuterostome vertebrates. However, little is known about the functions of VP/OT-type neuropeptide in deuterostome invertebrates especially in echinoderms. Here, we firstly report VP/OT-type neuropeptide signaling in an important economic species, , which is widely cultured in Asia, with high nutritional and medicinal values. Molecular characterization analysis of holotocin and its precursor revealed the highly conserved features of VP/OT family. The candidate receptor for holotocin (AjHOR) was confirmed to be able to activate the signaling via cAMP-PKA and possible Ca-PKC pathway, and further activated the downstream ERK1/2 cascade. Holotocin precursor expression profile showed that they were mainly concentrated in circumoral nerve ring. Furthermore, in vitro pharmacological experiments demonstrated that holotocin caused contractile responses in preparations from . And in vivo functional studies indicated that short-term injection of holotocin resulted in body bloat and long-term injection resulted in reduced body mass, suggesting potential roles of holotocin in osmoregulation and feeding co-inhibition with holotocin-CCK. Our findings provided a comprehensive description of AjHOR-holotocin signaling, revealed ancient roles of holotocin in osmoregulation and feeding inhibition by controlling muscle contractions.
PubMed: 37762661
DOI: 10.3390/ijms241814358 -
International Journal of Molecular... Sep 2023The renin-angiotensin-aldosterone system (RAAS) plays a crucial role in maintaining various physiological processes in the body, including blood pressure regulation,... (Review)
Review
The renin-angiotensin-aldosterone system (RAAS) plays a crucial role in maintaining various physiological processes in the body, including blood pressure regulation, electrolyte balance, and overall cardiovascular health. However, any compounds or drugs known to perturb the RAAS might have an additional impact on transmembrane ionic currents. In this retrospective review article, we aimed to present a selection of chemical compounds or medications that have long been recognized as interfering with the RAAS. It is noteworthy that these substances may also exhibit regulatory effects in different types of ionic currents. Apocynin, known to attenuate the angiotensin II-induced activation of epithelial Na channels, was shown to stimulate peak and late components of voltage-gated Na current (). Esaxerenone, an antagonist of the mineralocorticoid receptor, can exert an inhibitory effect on peak and late directly. Dexamethasone, a synthetic glucocorticoid, can directly enhance the open probability of large-conductance Ca-activated K channels. Sparsentan, a dual-acting antagonist of the angiotensin II receptor and endothelin type A receptors, was found to suppress the amplitude of peak and late effectively. However, telmisartan, a blocker of the angiotensin II receptor, was effective in stimulating the peak and late along with a slowing of the inactivation time course of the current. However, telmisartan's presence can also suppress the -mediated K current. Moreover, tolvaptan, recognized as an aquaretic agent that can block the vasopressin receptor, was noted to suppress the amplitude of the delayed-rectifier K current and the M-type K current directly. The above results indicate that these substances not only have an interference effect on the RAAS but also exert regulatory effects on different types of ionic currents. Therefore, to determine their mechanisms of action, it is necessary to gain a deeper understanding.
Topics: Angiotensin II; Blood Pressure; Glucocorticoids; Receptor, Endothelin A; Renin-Angiotensin System; Telmisartan; Humans
PubMed: 37762309
DOI: 10.3390/ijms241814007 -
Biomedicines Sep 2023Previously, we reported that intracerebroventricularly administered kisspeptin-13 (KP-13) induces anxiety-like behavior and activates the hypothalamic-pituitary-adrenal...
A Brain Region-Dependent Alteration in the Expression of Vasopressin, Corticotropin-Releasing Factor, and Their Receptors Might Be in the Background of Kisspeptin-13-Induced Hypothalamic-Pituitary-Adrenal Axis Activation and Anxiety in Rats.
Previously, we reported that intracerebroventricularly administered kisspeptin-13 (KP-13) induces anxiety-like behavior and activates the hypothalamic-pituitary-adrenal (HPA) axis in rats. In the present study, we aimed to shed light on the mediation of KP-13's stress-evoking actions. The relative gene expressions of the corticotropin-releasing factor ( and ) and arginine vasopressin ( and ) systems were measured in the amygdala and hippocampus of male Wistar rats after icv KP-13 treatment. CRF and AVP protein content were also determined. A different set of animals received CRF or V1 receptor antagonist pretreatment before the KP-13 challenge, after which either an open-field test or plasma corticosterone levels measurement was performed. In the amygdala, KP-13 induced an upregulation of and expression, and a downregulation of . In the hippocampus, the mRNA level of increased and the level of decreased. A significant rise in AVP protein content was also detected in the amygdala. KP-13 also evoked anxiety-like behavior in the open field test, which the V1 receptor blocker antagonized. Both CRF and V1 receptor blockers reduced the KP-13-evoked rise in the plasma corticosterone level. This suggests that KP-13 alters the AVP and CRF signaling and that might be responsible for its effect on the HPA axis and anxiety-like behavior.
PubMed: 37760887
DOI: 10.3390/biomedicines11092446 -
Clinics and Practice Aug 2023Tolvaptan, a selective vasopressin V2 receptor antagonist, is the first and only approved specific treatment for Autosomal-Dominant Polycystic Kidney Disease (ADPKD),...
Tolvaptan, a selective vasopressin V2 receptor antagonist, is the first and only approved specific treatment for Autosomal-Dominant Polycystic Kidney Disease (ADPKD), and is used in current clinical practice. Real clinical data are missing. In this retrospective study, 41 ADPKD patients received tolvaptan for 3 years, from 2018 to 2021. Total kidney volume (TKV) was measured using Magnetic Resonance Imaging, at initiation and at the end of the treatment period. A complete biochemistry/hematology profile and a 24 h urine volume collection were performed monthly for the first 18 months and every 3 months thereafter. At the end of the treatment period, the median (IQR) estimated Glomerular Filtration Rate (e-GFR) was 5.3 (-1.3, 8.7) mL/min higher than the expected e-GFR decline without treatment, while the prediction for End Stage Chronic Kidney Disease (ESKD) had been prolonged by 1 (0, 2) year. Total Kidney Volume did not change significantly (2250 (1357) mL at 3 years of treatment vs. 2180 (1091) mL expected without treatment, = 0.48). Younger patients with a relatively preserved e-GFR, lower hypertension burden, better familiar renal prognosis and more severe imaging data showed better outcomes. The aquaretic adverse effects of tolvaptan did not affect renal function and electrolyte balance in 51 patients, in a follow-up period of 18 months. Consequently, tolvaptan seems to be effective in preventing progression of ADPKD when administered in a timely manner in patients with better familiar renal history, shorter hypertension duration and worse imaging profile. Increased diuresis does not affect treatment efficacy.
PubMed: 37736928
DOI: 10.3390/clinpract13050092 -
World Journal of Clinical Cases Sep 2023Holoprosencephaly (HPE) is a congenital malformation with various degrees of incomplete separation of the cerebral hemispheres due to differentiation disorders of the...
BACKGROUND
Holoprosencephaly (HPE) is a congenital malformation with various degrees of incomplete separation of the cerebral hemispheres due to differentiation disorders of the forebrain. Although HPE with diabetes insipidus due to associated pituitary dysfunction has been reported, HPE with the syndrome of inappropriate antidiuretic hormone secretion (SIADH) is very rare. Tolvaptan, a vasopressin V2 receptor antagonist, is effective in adults with SIADH. However, there is no report of its efficacy in infants with SIADH. The purpose of this report is to demonstrate that tolvaptan is effective for SIADH in infants and that administration of tolvaptan eliminates the need for restriction of water intake and sodium administration.
CASE SUMMARY
A 2414-g female infant was born at 38 wk by normal vaginal delivery. Facial anomalies and head magnetic resonance imaging indicated semilobar HPE. After birth, she had hyponatremia due to SIADH and was treated using water and sodium restriction. However, she developed an exaggerated response to the fluid restrictions, resulting in large fluctuations in serum sodium levels. Subsequent administration of tolvaptan improved the fluctuations in serum sodium levels without the need for adjustment of water or sodium administration. Serum sodium was maintained within the normal range after discontinuation of tolvaptan at 80 d of life. There were no side effects, such as hypernatremia or liver dysfunction, during the administration of tolvaptan.
CONCLUSION
This is the first report on the safety and efficacy of tolvaptan in an infant with SIADH associated with HPE.
PubMed: 37731562
DOI: 10.12998/wjcc.v11.i26.6262 -
Biochemical and Biophysical Research... Nov 2023Many insects produce the cyclic neuropeptide inotocin (CLITNCPRGamide), which is the insect orthologue of the mammalian neuropeptides oxytocin and vasopressin. These...
Many insects produce the cyclic neuropeptide inotocin (CLITNCPRGamide), which is the insect orthologue of the mammalian neuropeptides oxytocin and vasopressin. These insects also have one inotocin G protein-coupled receptor (GPCR), which is the orthologue of the mammalian oxytocin and vasopressin receptors. The tick Ixodes scapularis belongs to the subphylum Chelicerata, an arthropod taxon different from insects, to which also spiders, scorpions, and mites belong. I. scapularis is an ectoparasite and a health risk for humans, because it transfers pathogenic microorganisms to its human host during a blood meal, thereby causing serious neurological diseases, among them Lyme disease and tick-borne encephalitis (TBE). By annotating the genomic sequence of I. scapularis, we previously found one presumed tick inotocin preprohormone gene and, in contrast to insects, three genes coding for presumed inotocin GPCRs. We now find that these GPCR genes cluster on one genomic contig, suggesting that they originated by recent gene duplications. Closely located on the same contig are also four adipokinetic hormone/corazonin-related peptide (ACP) GPCR genes, and one crustacean cardioactive peptide (CCAP) GPCR gene, suggesting evolutionary relationships. These evolutionary relationships are confirmed by phylogenetic tree analyses of their gene products. We also cloned the tick inotocin preprohormone, which has a structural organization closely resembling mammalian oxytocin and vasopressin preprohormones, including the presence of a conserved neurophysin sequence, having seven cystine bridges. This neurophysin sequence has two cystine-knot domains, but in contrast to mammalian neurophysins, the tick neurophysin contains a canonical prohormone convertase cleavage signal and a peptide C-terminal amidation sequence (GKR), suggesting cleavage into two biologically active cystine-knot peptides. This cleavage/amidation sequence occurs in neurophysins from most hard tick species, but not in other chelicerates. Mature tick inotocin is different from insect inotocin and has the sequence CFITNCPPGamide. Finally, we cloned and stably expressed the three tick inotocin receptors in Chinese Hamster Ovary cells and found that each of them was activated by nanomolar concentrations of tick inotocin (EC for ITR1 = 1.6 × 10 M; EC for ITR2 = 5.8 × 10 M; EC for ITR3 = 9.3 × 10 M), thereby establishing that they are genuine tick inotocin receptors.
PubMed: 37716155
DOI: 10.1016/j.bbrc.2023.09.009