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American Journal of Physiology. Renal... Nov 2018The antidiuretic hormone vasopressin (VP) is produced by the hypothalamus and is stored and secreted from the posterior pituitary. VP acts via VP type 2 receptors (V2Rs)... (Review)
Review
The antidiuretic hormone vasopressin (VP) is produced by the hypothalamus and is stored and secreted from the posterior pituitary. VP acts via VP type 2 receptors (V2Rs) on the basolateral membrane of principal cells of the collecting duct (CD) to regulate fluid permeability. The VP-evoked endocrine pathway is essential in determining urine concentrating capability. For example, a defect in any component of the VP signaling pathway can result in polyuria, polydipsia, and hypotonic urine, collectively termed diabetes insipidus (DI). A lack of VP production precipitates central diabetes insipidus (CDI), which can be managed effectively by VP supplementation. A majority of cases of nephrogenic diabetes insipidus (NDI) result from V2R mutations that impair receptor sensitivity. No specific therapy is currently available for management of NDI. Evidence is evolving that (pro)renin receptor (PRR), a newly identified member of the renin-angiotensin system, is capable of regulating VP production and action. As such, PRR should be considered strongly as a therapeutic target for treating CDI and NDI. The current review will summarize recent advances in understanding the physiology of renal and central PRR as it relates to the two types of DI.
Topics: Animals; Antidiuretic Agents; Diabetes Insipidus; Diuresis; Genetic Predisposition to Disease; Humans; Kidney; Mutation; Phenotype; Receptors, Cell Surface; Receptors, Vasopressin; Renin-Angiotensin System; Vasopressins; Prorenin Receptor
PubMed: 30019932
DOI: 10.1152/ajprenal.00266.2018 -
Journal of Diabetes and Its... Jan 2021The endoplasmic reticulum (ER) lies at the crossroads of protein folding, calcium storage, lipid metabolism, and the regulation of autophagy and apoptosis. Accordingly,...
The endoplasmic reticulum (ER) lies at the crossroads of protein folding, calcium storage, lipid metabolism, and the regulation of autophagy and apoptosis. Accordingly, dysregulation of ER homeostasis leads to β-cell dysfunction in type 1 and type 2 diabetes that ultimately culminates in cell death. The ER is therefore an emerging target for understanding the mechanisms of diabetes mellitus that captures the complex etiologies of this multifactorial class of metabolic disorders. Our strategy for developing ER-targeted diagnostics and therapeutics is to focus on monogenic forms of diabetes related to ER dysregulation in an effort to understand the exact contribution of ER stress to β-cell death. In this manner, we can develop personalized genetic medicine for ERstress-related diabetic disorders, such as Wolfram syndrome. In this article, we describe the phenotypes and molecular pathogenesis of ERstress-related monogenic forms of diabetes.
Topics: Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Endoplasmic Reticulum; Endoplasmic Reticulum Stress; Humans; Insulin-Secreting Cells; Wolfram Syndrome
PubMed: 32518033
DOI: 10.1016/j.jdiacomp.2020.107618 -
ELife Jan 2023Wolfram syndrome 1 (WS1) is a rare genetic disorder caused by mutations in the gene leading to a wide spectrum of clinical dysfunctions, among which blindness,...
Wolfram syndrome 1 (WS1) is a rare genetic disorder caused by mutations in the gene leading to a wide spectrum of clinical dysfunctions, among which blindness, diabetes, and neurological deficits are the most prominent. encodes for the endoplasmic reticulum (ER) resident transmembrane protein wolframin with multiple functions in ER processes. However, the -dependent etiopathology in retinal cells is unknown. Herein, we showed that mutant mice developed early retinal electrophysiological impairments followed by marked visual loss. Interestingly, axons and myelin disruption in the optic nerve preceded the degeneration of the retinal ganglion cell bodies in the retina. Transcriptomics at pre-degenerative stage revealed the STAT3-dependent activation of proinflammatory glial markers with reduction of the homeostatic and pro-survival factors glutamine synthetase and BDNF. Furthermore, label-free comparative proteomics identified a significant reduction of the monocarboxylate transport isoform 1 (MCT1) and its partner basigin that are highly enriched on retinal glia and myelin-forming oligodendrocytes in optic nerve together with wolframin. Loss of MCT1 caused a failure in lactate transfer from glial to neuronal cell bodies and axons leading to a chronic hypometabolic state. Thus, this bioenergetic impairment is occurring concurrently both within the axonal regions and cell bodies of the retinal ganglion cells, selectively endangering their survival while impacting less on other retinal cells. This metabolic dysfunction occurs months before the frank RGC degeneration suggesting an extended time-window for intervening with new therapeutic strategies focused on boosting retinal and optic nerve bioenergetics in WS1.
Topics: Animals; Mice; Nerve Degeneration; Neuroinflammatory Diseases; Optic Atrophy; Retinal Ganglion Cells; Wolfram Syndrome
PubMed: 36645345
DOI: 10.7554/eLife.81779 -
Cells Sep 2020As a rare hereditary disease, congenital nephrogenic diabetes insipidus (NDI) is clinically characterized by polyuria with hyposthenuria and polydipsia. NDI results from... (Review)
Review
As a rare hereditary disease, congenital nephrogenic diabetes insipidus (NDI) is clinically characterized by polyuria with hyposthenuria and polydipsia. NDI results from collecting duct principal cell hyporesponsiveness or insensitivity to the antidiuretic action of arginine vasopressin (AVP). The principal cell-specific water channel aquaporin-2 (AQP2) plays an essential role in water reabsorption along osmotic gradients. The capacity to accumulate AQP2 in the apical plasma membrane in response to decreased fluid volume or increased plasma osmolality is critically regulated by the antidiuretic hormone AVP and its receptor 2 (AVPR2). Mutations in result in X-linked recessive NDI, the most common form of inherited NDI. Genetic defects in cause autosomal recessive or dominant NDI. In this review, we provide an updated overview of the genetic and molecular mechanisms of congenital NDI, with a focus on the potential disease-causing mutations in and , the molecular defects in the AVPR2 and AQP2 mutants, post-translational modifications (i.e., phosphorylation, ubiquitination, and glycosylation) and various protein-protein interactions that regulate phosphorylation, ubiquitination, tetramerization, trafficking, stability, and degradation of AQP2.
Topics: Aquaporin 2; Diabetes Insipidus, Nephrogenic; Humans; Mutation; Neurophysins; Polyuria; Protein Interaction Maps; Protein Precursors; Protein Processing, Post-Translational; Protein Transport; Receptors, Vasopressin; Vasopressins
PubMed: 32993088
DOI: 10.3390/cells9102172 -
Hormone Research in Paediatrics 2021Langerhans cell histiocytosis (LCH) is a disorder of the mononuclear phagocyte system that can affect almost any organ and system. The most common central nervous system... (Review)
Review
Langerhans cell histiocytosis (LCH) is a disorder of the mononuclear phagocyte system that can affect almost any organ and system. The most common central nervous system (CNS) manifestation in LCH is the infiltration of the hypothalamic-pituitary region leading to destruction and neurodegeneration of CNS tissue. The latter causes the most frequent endocrinological manifestation, that is, central diabetes insipidus (CDI), and less often anterior pituitary hormone deficiency (APD). The reported incidence of CDI is estimated between 11.5 and 24% and is considered a risk factor for neurodegenerative disease and APD. Three risk factors for development of CDI are recognized in the majority of the studies: (1) multisystem disease, (2) the occurrence of reactivations or active disease for a prolonged period, and (3) the presence of craniofacial bone lesions. Since CDI may occur as the first manifestation of LCH, differential diagnosis of malignant diseases like germ cell tumours must be made. APD is almost always associated with CDI and can appear several years after the diagnosis of CDI. Growth hormone is the most commonly affected anterior pituitary hormone. Despite significant advances in the knowledge of LCH in recent years, little progress has been made in preventing long-term sequelae such as those affecting the hypothalamic-pituitary system.
Topics: Child; Diabetes Insipidus, Neurogenic; Histiocytosis, Langerhans-Cell; Humans; Hypopituitarism
PubMed: 34167121
DOI: 10.1159/000517040 -
So-called bifocal tumors with diabetes insipidus and negative tumor markers: are they all germinoma?Neuro-oncology Feb 2021The Delphi consensus statements on the management of germ cell tumors (GCTs) failed to reach agreements on the statement that the cases with (i) pineal and...
BACKGROUND
The Delphi consensus statements on the management of germ cell tumors (GCTs) failed to reach agreements on the statement that the cases with (i) pineal and neurohypophyseal bifocal lesion, (ii) with diabetes insipidus, and (iii) with negative tumor markers can be diagnosed as germinoma without histological verification. To answer this, multicenter retrospective analysis was performed.
METHODS
A questionnaire on clinical findings, histological diagnosis, and details of surgical procedures was sent to 86 neurosurgical and 35 pediatrics departments in Japan.
RESULTS
Fifty-one institutes reported 132 cases that fulfilled the 3 criteria. Tissue sampling was performed in 91 cases from pineal (n = 44), neurohypophyseal (n = 32), both (n = 6), and distant (n = 9) lesions. Histological diagnosis was established in 89 cases: pure germinoma or germinoma with syncytiotrophoblastic giant cells in 82 (92.1%) cases, germinoma and mature teratoma in 2 cases, and granulomatous inflammation in 2 cases. Histological diagnosis was not established in 2 cases. Although no tumors other than GCTs were identified, 3 (3.4%) patients had non-germinomatous GCTs (NGGCTs). None of the patients developed permanent complications after endoscopic or stereotactic biopsy. Thirty-nine patients underwent simultaneous procedure for acute hydrocephalus without permanent complications, and hydrocephalus was controlled in 94.9% of them.
CONCLUSION
All patients who fulfilled the 3 criteria had GCTs or granulomatous inflammation, but not other types of tumors. However, no fewer than 3.4% of the patients had NGGCTs. Considering the safety and the effects of simultaneous procedures for acute hydrocephalus, biopsy was recommended in such patients.
Topics: Biomarkers, Tumor; Brain Neoplasms; Child; Diabetes Insipidus; Diabetes Mellitus; Germinoma; Humans; Male; Pineal Gland; Retrospective Studies
PubMed: 32818237
DOI: 10.1093/neuonc/noaa199 -
Journal of Cellular and Molecular... Feb 2015Statins competitively inhibit hepatic 3-hydroxy-3-methylglutaryl-coenzyme A reductase, resulting in reduced plasma total and low-density lipoprotein cholesterol levels.... (Review)
Review
Statins competitively inhibit hepatic 3-hydroxy-3-methylglutaryl-coenzyme A reductase, resulting in reduced plasma total and low-density lipoprotein cholesterol levels. Recently, it has been shown that statins exert additional 'pleiotropic' effects by increasing expression levels of the membrane water channels aquaporin 2 (AQP2). AQP2 is localized mainly in the kidney and plays a critical role in determining cellular water content. This additional effect is independent of cholesterol homoeostasis, and depends on depletion of mevalonate-derived intermediates of sterol synthetic pathways, i.e. farnesylpyrophosphate and geranylgeranylpyrophosphate. By up-regulating the expression levels of AQP2, statins increase water reabsorption by the kidney, thus opening up a new avenue in treating patients with nephrogenic diabetes insipidus (NDI), a hereditary disease that yet lacks high-powered and limited side effects therapy. Aspects related to water balance determined by AQP2 in the kidney, as well as standard and novel therapeutic strategies of NDI are discussed.
Topics: Animals; Aquaporin 2; Diabetes Insipidus, Nephrogenic; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Kidney
PubMed: 25594563
DOI: 10.1111/jcmm.12422 -
Journal of the American Society of... Oct 2016
Topics: Aquaporin 2; Diabetes Insipidus, Nephrogenic; Humans; Receptors, Cell Surface; Receptors, Vasopressin; Prorenin Receptor
PubMed: 27098238
DOI: 10.1681/ASN.2016030344 -
Frontiers in Endocrinology 2022Wolfram syndrome is a rare genetic disorder characterized by juvenile-onset diabetes mellitus, optic nerve atrophy, hearing loss, diabetes insipidus, and progressive...
Wolfram syndrome is a rare genetic disorder characterized by juvenile-onset diabetes mellitus, optic nerve atrophy, hearing loss, diabetes insipidus, and progressive neurodegeneration. Pathogenic variants in the gene are the main causes of Wolfram syndrome. encodes a transmembrane protein localized to the endoplasmic reticulum (ER) and regulates the unfolded protein response (UPR). Loss of function of leads to dysregulation of insulin production and secretion, ER calcium depletion, and cytosolic calpains activation, resulting in activation of apoptotic cascades. Although the terminal UPR has been shown to induce inflammation that accelerates pancreatic β-cell dysfunction and death in diabetes, the contribution of pancreatic β-cell inflammation to the development of diabetes in Wolfram syndrome has not been fully understood. Here we show that -deficiency enhances the gene expression of pro-inflammatory cytokines and chemokines, leading to cytokine-induced ER-stress and cell death in pancreatic β-cells. PERK and IRE1α pathways mediate high glucose-induced inflammation in a β-cell model of Wolfram syndrome. M1-macrophage infiltration and hypervascularization are seen in the pancreatic islets of whole-body knockout mice, demonstrating that WFS1 regulates anti-inflammatory responses in pancreatic β-cells. Our results indicate that inflammation plays an essential role in the progression of β-cell death and diabetes in Wolfram syndrome. The pathways involved in ER stress-mediated inflammation provide potential therapeutic targets for the treatment of Wolfram syndrome.
Topics: Animals; Endoplasmic Reticulum Stress; Endoribonucleases; Inflammation; Insulin-Secreting Cells; Loss of Function Mutation; Membrane Proteins; Mice; Protein Serine-Threonine Kinases; Wolfram Syndrome
PubMed: 35399956
DOI: 10.3389/fendo.2022.849204 -
Orphanet Journal of Rare Diseases Feb 2020Wolfram syndrome is a rare genetic disease characterized by insulin-dependent diabetes, optic nerve atrophy, sensorineural hearing loss and neurodegeneration. Although...
BACKGROUND
Wolfram syndrome is a rare genetic disease characterized by insulin-dependent diabetes, optic nerve atrophy, sensorineural hearing loss and neurodegeneration. Although olfactory dysfunction, a classical clinical marker of neurodegenerative processes, has been reported in Wolfram syndrome, its use as a clinical marker in Wolfram is limited due to data scarcity. In addition, it is unknown whether Wolfram syndrome affects the sense of taste.
METHODS
Smell and taste perception were assessed in participants with Wolfram syndrome (n = 40) who were 15.1 ± 6.0 years of age (range: 5.1-28.7 years) and two sex- and age-matched control groups: one group with type 1 diabetes mellitus (T1D; n = 25) and a healthy control group (HC; n = 29). Smell sensitivity was assessed by measuring n-butanol detection thresholds and smell identification by using the University of Pennsylvania Smell Identification Test (UPSIT). Taste function was assessed using NIH Toolbox, which includes the assessment of sucrose (sweet) taste preference, and perceived intensity of sucrose, sodium chloride (salty), and quinine hydrochloride (bitter) both in the tip of the tongue (regional test) and the whole mouth.
RESULTS
Smell sensitivity was not significantly different among groups; however, smell identification was impaired in Wolfram syndrome, as reflected by significantly lower UPSIT scores in Wolfram syndrome compared to HC and T1D (P < 0.001). Compared to participants in the control groups, participants with Wolfram syndrome had a blunted perception of sweetness and saltiness when taste stimuli were applied regionally (P < 0.05), but differences in perceived intensity were no longer significant among groups when taste stimuli were tasted with the whole mouth. Groups preferred similar sucrose concentrations.
CONCLUSION
Wolfram syndrome was associated with olfactory dysfunction. However, the olfactory dysfunction was qualitative (related to smell identification) and not secondary to olfactory insensitivity or diabetes, suggesting is arising from dysfunction in central olfactory brain regions. In contrast to olfaction, and despite decreased perception of taste intensity in the anterior tongue, the sense of taste was overall well-conserved in individuals with Wolfram syndrome. Future longitudinal studies of taste and smell perception in Wolfram syndrome will be important to determine the use of the chemical senses as clinical markers of disease progression.
Topics: Adolescent; Adult; Biomarkers; Child; Child, Preschool; Humans; Smell; Taste; Wolfram Syndrome; Young Adult
PubMed: 32087739
DOI: 10.1186/s13023-020-1335-7