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1.
EMBO J ; 40(14): e107294, 2021 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-34031912

RESUMO

Potassium-coupled chloride transporters (KCCs) play crucial roles in regulating cell volume and intracellular chloride concentration. They are characteristically inhibited under isotonic conditions via phospho-regulatory sites located within the cytoplasmic termini. Decreased inhibitory phosphorylation in response to hypotonic cell swelling stimulates transport activity, and dysfunction of this regulatory process has been associated with various human diseases. Here, we present cryo-EM structures of human KCC3b and KCC1, revealing structural determinants for phospho-regulation in both N- and C-termini. We show that phospho-mimetic KCC3b is arrested in an inward-facing state in which intracellular ion access is blocked by extensive contacts with the N-terminus. In another mutant with increased isotonic transport activity, KCC1Δ19, this interdomain interaction is absent, likely due to a unique phospho-regulatory site in the KCC1 N-terminus. Furthermore, we map additional phosphorylation sites as well as a previously unknown ATP/ADP-binding pocket in the large C-terminal domain and show enhanced thermal stabilization of other CCCs by adenine nucleotides. These findings provide fundamentally new insights into the complex regulation of KCCs and may unlock innovative strategies for drug development.


Assuntos
Cloretos/metabolismo , Nucleotídeos/metabolismo , Potássio/metabolismo , Simportadores/metabolismo , Animais , Linhagem Celular , Tamanho Celular , Humanos , Fosforilação/fisiologia , Células Sf9 , Transdução de Sinais/fisiologia , Cotransportadores de K e Cl-
2.
J Cell Physiol ; 237(12): 4356-4368, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-36125923

RESUMO

Bone turnover diseases are exceptionally prevalent in human and come with a high burden on physical health. While these diseases are associated with a variety of risk factors and causes, they are all characterized by common denominators, that is, abnormalities in the function or number of osteoblasts, osteoclasts, and/or osteocytes. As such, much effort has been deployed in the recent years to understand the signaling mechanisms of bone cell proliferation and differentiation with the objectives of exploiting the intermediates involved as therapeutic preys. Ion transport systems at the external and in the intracellular membranes of osteoblasts and osteoclasts also play an important role in bone turnover by coordinating the movement of Ca2+ , PO4 2- , and H+ ions in and out of the osseous matrix. Even if they sustain the terminal steps of osteoformation and osteoresorption, they have been the object of very little attention in the last several years. Members of the cation-Cl- cotransporter (CCC) family are among the systems at work as they are expressed in bone cells, are known to affect the activity of Ca2+ -, PO4 2- -, and H+ -dependent transport systems and have been linked to bone mass density variation in human. In this review, the roles played by the CCCs in bone remodeling will be discussed in light of recent developments and their potential relevance in the treatment of skeletal disorders.


Assuntos
Osteócitos , Simportadores , Humanos , Cátions/metabolismo , Transporte de Íons/fisiologia , Osteócitos/metabolismo , Simportadores de Cloreto de Sódio-Potássio/metabolismo , Simportadores/metabolismo , Remodelação Óssea , Densidade Óssea
3.
Mol Psychiatry ; 26(9): 5441-5463, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-32514103

RESUMO

Huntington's disease (HD) is a monogenic neurodegenerative disorder resulting from a mutation in the huntingtin gene. This leads to the expression of the mutant huntingtin protein (mHTT) which provokes pathological changes in both the central nervous system (CNS) and periphery. Accumulating evidence suggests that mHTT can spread between cells of the CNS but here, we explored the possibility that mHTT could also propagate and cause pathology via the bloodstream. For this, we used a parabiosis approach to join the circulatory systems of wild-type (WT) and zQ175 mice. After surgery, we observed mHTT in the plasma and circulating blood cells of WT mice and post-mortem analyses revealed the presence of mHTT aggregates in several organs including the liver, kidney, muscle and brain. The presence of mHTT in the brain was accompanied by vascular abnormalities, such as a reduction of Collagen IV signal intensity and altered vessel diameter in the striatum, and changes in expression of Glutamic acid decarboxylase 65/67 (GAD65-67) in the cortex. Conversely, we measured reduced pathology in zQ175 mice by decreased mitochondrial impairments in peripheral organs, restored vessel diameter in the cortex and improved expression of Dopamine- and cAMP-regulated phosphoprotein 32 (DARPP32) in striatal neurons. Collectively, these results demonstrate that circulating mHTT can disseminate disease, but importantly, that healthy blood can dilute pathology. These findings have significant implications for the development of therapies in HD.


Assuntos
Doença de Huntington , Animais , Corpo Estriado/metabolismo , Modelos Animais de Doenças , Fosfoproteína 32 Regulada por cAMP e Dopamina , Proteína Huntingtina/genética , Proteína Huntingtina/metabolismo , Doença de Huntington/genética , Camundongos , Camundongos Transgênicos , Neurônios/metabolismo
4.
J Cell Physiol ; 236(3): 1712-1729, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-32776569

RESUMO

Na+ -K+ -Cl- cotransporter 2 (NKCC2; SLC12A1) is an integral membrane protein that comes as three splice variants and mediates the cotranslocation of Na+ , K+ , and Cl- ions through the apical membrane of the thick ascending loop of Henle (TALH). In doing so, and through the involvement of other ion transport systems, it allows this nephron segment to reclaim a large fraction of the ultrafiltered Na+ , Cl- , Ca2+ , Mg2+ , and HCO3- loads. The functional relevance of NKCC2 in human is illustrated by the many abnormalities that result from the inactivation of this transport system through the use of loop diuretics or in the setting of inherited disorders. The following presentation aims at discussing the physiological roles and molecular characteristics of Na+ -K+ -Cl- cotransport in the TALH and those of the individual NKCC2 splice variants more specifically. Many of the historical and recent data that have emerged from the experiments conducted will be outlined and their larger meaning will also be placed into perspective with the aid of various hypotheses.


Assuntos
Membro 3 da Família 12 de Carreador de Soluto/metabolismo , Processamento Alternativo/genética , Sequência de Aminoácidos , Animais , Humanos , Transporte de Íons , Alça do Néfron/metabolismo , Modelos Biológicos , Membro 3 da Família 12 de Carreador de Soluto/química , Membro 3 da Família 12 de Carreador de Soluto/genética
5.
Am J Physiol Cell Physiol ; 317(1): C20-C30, 2019 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-30917032

RESUMO

Na+-K+-Cl- cotransporter type 2 (NKCC2) is confined to the apical membrane of the thick ascending limb of Henle, where it reabsorbs a substantial fraction of the ultrafiltered NaCl load. It is expressed along this nephron segment as three main splice variants (called NKCC2A, NKCC2B, and NKCC2F) that differ in residue composition along their second transmembrane domain and first intracellular cytosolic connecting segment (CS2). NKCC2 is known to be activated by cell shrinkage and intracellular [Cl-] reduction. Although the with no lysine (WNK) kinases could play a role in this response, the mechanisms involved are ill defined, and the possibility of variant-specific responses has not been tested thus far. In this study, we have used the Xenopus laevis oocyte expression system to gain further insight in these regards. We have found for the first time that cell shrinkage could stimulate NKCC2A- and NKCC2B-mediated ion transport by increasing carrier abundance at the cell surface and that this response was achieved (at least in part) by the enzymatic function of a WNK kinase. Interestingly, we have also found that the activity and cell surface abundance of NKCC2F were less affected by cell shrinkage compared with the other variants and that ion transport by certain variants could be stimulated through WNK kinase expression in the absence of carrier redistribution. Taken together, these results suggest that the WNK kinase-dependent pathway can affect both the trafficking as well as intrinsic activity of NKCC2 and that CS2 plays an important role in carrier regulation.


Assuntos
Rim/enzimologia , Proteínas Serina-Treonina Quinases/metabolismo , Reabsorção Renal , Membro 1 da Família 12 de Carreador de Soluto/metabolismo , Proteína Quinase 1 Deficiente de Lisina WNK/metabolismo , Animais , Tamanho Celular , Endocitose , Glicosilação , Transporte de Íons , Cinética , Camundongos , Oócitos , Fosforilação , Proteínas Serina-Treonina Quinases/genética , Transporte Proteico , Coelhos , Membro 1 da Família 12 de Carreador de Soluto/genética , Proteína Quinase 1 Deficiente de Lisina WNK/genética , Xenopus laevis
6.
J Physiol ; 597(16): 4263-4276, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31216057

RESUMO

KEY POINTS: Na+ -K+ -Cl- cotransporter type 2 (NKCC2) is a 27-exon membrane protein that is expressed in the thick ascending limb (TAL) of Henle where it is involved in reabsorption of the ultrafiltered NaCl load. It comes as three splice variants that are identical to each other except for the residue composition of exon 4 and that differ in their transport characteristics, functional roles and distributions along the TAL. In this report, it is shown that the variants also differ in their trafficking properties and that two residues in exon 4 play a key role in this regard. One of these residues was also shown to sustain carrier internalization. Through these results, a novel function for the alternatively spliced exon of NKCC2 has been identified and a domain that is involved in carrier trafficking has been uncovered for the first time in a cation-Cl- cotransporter family member. ABSTRACT: Na+ -K+ -Cl- cotransporter type 2 (NKCC2) is a 12-transmembrane (TM) domain cell surface glycoprotein that is expressed in the thick ascending limb (TAL) of Henle and stimulated during cell shrinkage. It comes as three splice variants (A, B and F) that are identical to each other except for TM2 and the following connecting segment (CS2). Yet, these variants do not share the same localization, transport characteristics and physiological roles along the TAL. We have recently found that while cell shrinkage could exert its activating effect by increasing NKCC2 expression at the cell surface, the variants also responded differentially to this stimulus. In the current work, a mutagenic approach was exploited to determine whether CS2 could play a role in carrier trafficking and identify the residues potentially involved. We found that when the residue of position 238 in NKCC2A (F) and NKCC2B (Y) was replaced by the corresponding residue in NKCC2F (V), carrier activity increased by over 3-fold and endocytosis decreased concomitantly. We also found that when the residue of position 230 in NKCC2F (M) was replaced by the one in NKCC2B (T), carrier activity and affinity for ions both increased substantially whereas expression at the membrane decreased. Taken together, these results suggest that CS2 is involved in carrier trafficking and that two of its residues, those of positions 238 and 230, are part of an internalization motif. They also indicate that the divergent residue of position 230 plays the dual role of specifying ion affinity and sustaining carrier internalization.


Assuntos
Simportadores de Cloreto de Sódio-Potássio/metabolismo , Processamento Alternativo , Animais , Sequência de Bases , Membrana Celular , Éxons , Regulação da Expressão Gênica/fisiologia , Oócitos , Conformação Proteica , Transporte Proteico/fisiologia , Simportadores de Cloreto de Sódio-Potássio/classificação , Simportadores de Cloreto de Sódio-Potássio/genética , Xenopus laevis
7.
J Cell Physiol ; 233(1): 396-408, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28276587

RESUMO

The K+ -Cl- cotransporters (KCCs) belong to the cation-Cl- cotransporter family and consist of four isoforms and many splice variants. Their main role is to promote electroneutral efflux of K+ and Cl- ions across the surface of many cell types and, thereby, to regulate intracellular ion concentration, cell volume, and epithelial salt movement. These transport systems are induced by an increase in cell volume and are less active at lower intracellular [Cl- ] (Cli ), but the mechanisms at play are still ill-defined. In this work, we have exploited the Xenopus laevis expression system to study the role of lysine-deficient protein kinases (WNKs), protein phosphatases 1 (PP1s), and SPS1-related proline/alanine-rich kinase (SPAK) in KCC4 regulation during cell swelling. We have found that WNK4 and PP1 regulate KCC4 activity as part of a common signaling module, but that they do not exert their effects through SPAK or carrier dephosphorylation. We have also found that the phosphatases at play include PP1α and PP1γ1, but that WNK4 acts directly on the PP1s instead of the opposite. Unexpectedly, however, both cell swelling and a T926A substitution in the C-terminus of full-length KCC4 led to higher levels of heterologous K+ -Cl- cotransport and overall carrier phosphorylation. These results imply that the response to cell swelling must also involve allosteric-sensitive kinase-dependent phosphoacceptor sites in KCC4. They are thus partially inconsistent with previous models of KCC regulation.


Assuntos
Tamanho Celular , Proteína Fosfatase 1/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Simportadores/metabolismo , Animais , Tamanho Celular/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Toxinas Marinhas , Mutação , Oxazóis/farmacologia , Fosforilação , Proteína Fosfatase 1/antagonistas & inibidores , Proteína Fosfatase 1/genética , Processamento de Proteína Pós-Traducional , Proteínas Serina-Treonina Quinases/genética , Transdução de Sinais , Simportadores/efeitos dos fármacos , Simportadores/genética , Xenopus laevis , Cotransportadores de K e Cl-
8.
J Cell Physiol ; 233(10): 6369-6376, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29323714

RESUMO

Silicon (Si) is increasingly recognized as an essential trace element in animals, especially since the identification of mammalian Si transport systems and Si responsive genes not long ago. During many years, however, efforts to gain substantial insight into the biological role of this element in animals have achieved partial success due in part to the unavailability of validated protocols to study Si movement across biological membranes. To circumvent such limitations, we have developed a general transport assay in which cellular Si content was determined by automated electrothermal atomic absorption spectrophotometry. We have found this assay to provide great analytic sensitivity with Si detection thresholds of less than 1 µM, that is, below or very close to the concentration range of animal cells. We have also found this assay to provide valid and cost-effective determinations in Si transport studies while requiring workable quantities of samples. The protocol described here should thus become gold standard toward accelerated progress in the field of Si transport.


Assuntos
Aquaporinas/genética , Membrana Celular/metabolismo , Silício/metabolismo , Oligoelementos/metabolismo , Animais , Transporte Biológico/genética , Membrana Celular/genética , Regulação da Expressão Gênica , Células HEK293 , Humanos , Oócitos/citologia , Silício/química , Espectrofotometria Atômica , Oligoelementos/química , Xenopus laevis/metabolismo
11.
J Nephrol ; 37(3): 769-772, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38668984

RESUMO

Alport syndrome has been linked to three different genes, that is, COL4A3, COL4A4 and COL4A5. It is characterized by progressive and non-specific glomerulosclerosis with irregular thickening of the glomerular basement membrane (GBM). At times, the histopathologic picture is dominated by lesions that are consistent with focal and segmental glomerulosclerosis or IgA nephropathy. Here, we report the cases of two related individuals (mother and son) who were diagnosed with COL4A5-related Alport syndrome due to a missense variant (p.Gly1170Ser) in a G-X-Y repeat and found to present the same highly unusual histopathological abnormalities on their kidney biopsies. One of the abnormalities shared, which does not appear to have been reported, was reduced COL4A5 immunolabeling that was limited to Bowman's capsule even though the ultrastructure of the GBM was distorted. The other abnormality was superimposed segmental IgA deposition in both individuals, accompanied by mesangial changes in the mother. We feel that these findings provide novel insight into the mechanisms of disease manifestation in Alport syndrome. They suggest, in particular, that collagen expression and/or assemblies in Bowman's capsule is more vulnerable to missense mutations in COL4A5 than elsewhere in the kidney. Our findings also suggest that certain coinherited gene polymorphisms act as unexpectedly important phenotypic determinants in COL4A-related disorders.


Assuntos
Colágeno Tipo IV , Membrana Basal Glomerular , Mutação de Sentido Incorreto , Nefrite Hereditária , Adulto , Humanos , Pessoa de Meia-Idade , Biópsia , Cápsula Glomerular/patologia , Colágeno Tipo IV/genética , Predisposição Genética para Doença , Membrana Basal Glomerular/patologia , Membrana Basal Glomerular/ultraestrutura , Imunoglobulina A , Nefrite Hereditária/genética , Nefrite Hereditária/patologia , Linhagem , Fenótipo
14.
J Mol Med (Berl) ; 101(10): 1229-1236, 2023 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-37584739

RESUMO

RMND1 has been identified as a mitochondriopathy-associated gene less than 12 years ago. The most common phenotype related to this gene is an early onset, severe form of encephalomyopathy that leads to death in a medium time of three years after birth. However, milder and later onset presentations have been reported in some individuals, including two in whom the mitochondriopathy was identified at ~ 40 years of age, and the early onset presentations have been the object of no reports in those who survived beyond age 10. It is thus unclear how lethal RMND1-related conditions really are. We herein describe the oldest case to have been identified hitherto with this condition, i.e., that of a white female who was 61 at the time of diagnosis but was still active in her everyday life. The gene defect identified was nonetheless associated with many manifestations including ovarian insufficiency and sensorineural hearing loss (two features of what is currently designated as Perrault syndrome) as well as chronic renal failure, asymptomatic myopathy, leukopenia, and a few others. In our opinion, this case is of great translational interest for at least three reasons. First, it hints towards the possibility of near-normal life expectancies in some if not many individuals with RMND1 insufficiency. Second, it underlines the wide clinical spectrum associated with this gene. Third, it brings us to question the use of eponyms and syndromic features to identify the true etiology of multisystemic phenotypes. KEY MESSAGES: RMND1-related conditions typically manifest at an early age with a progressive and lethal form of encephalomyopathy. More benign presentations have been described with some being categorized as Perrault syndrome but none have been diagnosed after the age of 45. The clinical spectrum and presenting age of RMND1-related mitochondriopathies are probably much more varied than implied in the current literature. The case reported in this manuscript illustrates the limitedness of phenotype-based classifications of genetic disorders to identify the defect at cause.

15.
Can J Kidney Health Dis ; 9: 20543581221130686, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36406868

RESUMO

Rationale: Severe hyponatremia can lead to dramatic complications whether it is treated or not. At times, it may be very severe (serum Na concentration: NaS < 115 mmol/L) or even extreme (NaS < 105 mmol/L)a and its cause difficult to identify, especially in younger individuals with no history of water disorders. The case presented herein illustrates these points quite eloquently and leads us to believe that the current recommendations for the treatment of very severe hyponatremia require some fine-tuning. Presenting Concerns: A 26-year-old man was admitted to our intensive care unit for a NaS of 88 mmol/L in the absence of obvious extracellular fluid volume contraction. He had been experiencing vomiting, diarrhea, fatigue, and excessive thirst for the past 6 weeks and minor neurological symptoms just before admission. Laboratory tests at presentation also showed a urine osmolarity of 697 mOsm/L and urine Na of 40 mmol/L. Diagnoses: The presenting concerns were consistent with syndrome of inappropriate antidiuretic hormone secretion (SIADH) manifesting as extreme, yet mildly symptomatic hyponatremia. At the same time, they did not point toward a specific cause initially. Interventions: The patient was treated through water restriction, subcutaneous desmopressin, and various intravenous (IV) fluids. Our goal had been to increase NaS at a rate of 4 to 6 mmol/L/day and required the amount of NaCl and free water perfused hourly to be readjusted constantly. Access to water also had to be opposed as the patient was unable to tolerate his thirst. Outcomes: During the first 6 days, the rate of NaS correction achieved was ~6 mmol/L/day. The patient improved initially but at the end of day 6, he experienced severe extrapontine osmotic demyelination (with widespread pyramidal and extrapyramidal deficits) that did not respond to intravenous immunoglobulin and NaS relowering. A little more than 3 weeks later, he began to develop low blood pressure and a subfebrile state that revealed secondary to severe Addison disease. The water disorder and insatiable thirst subsided gradually upon replacing the deficient hormones but the neurological disorder went on to become permanent and highly disabling. Teaching points: (1) Very severe hyponatremia should always be handled as an emergency and monitored stringently in view of its potential to cause irreparable damage. (2) Because it is a major risk factor for osmotic demyelination, it should probably be corrected at a rate of less than 4 mmol/L/day especially if it is in the extreme range, chronic, or of unknown duration. (3) It can be a presenting manifestation of Addison disease.


Justification: Qu'elle soit traitée ou non, l'hyponatrémie grave peut entraîner des complications dramatiques. L'hyponatrémie peut être très grave (concentration de Na sérique : NaS < 115 mmol/L), voire extrême (NaS < 105 mmol/L)a, et sa cause peut être difficile à identifier, particulièrement chez les sujets plus jeunes sans antécédents de déséquilibres hydriques. Le cas présenté illustre ces points de façon éloquente et nous porte à croire que les recommandations actuelles pour le traitement de l'hyponatrémie très grave nécessitent un ajustement. Présentation du cas: Un homme de 26 ans a été admis à notre unité de soins intensifs pour une NaS de 88 mmol/L sans contraction évidente du volume liquidien extracellulaire. Le patient avait souffert de vomissements, de diarrhée, de fatigue et de soif excessive au cours des six dernières semaines, et de symptômes neurologiques mineurs juste avant son admission. Les analyses de laboratoire à la présentation montraient également une osmolarité urinaire à 697 mOsm/L et une concentration de Na urinaire à 40 mmol/L. Diagnostic: Les symptômes à la présentation étaient compatibles avec un SIADH se manifestant par une hyponatrémie extrême, bien que peu symptomatique. En même temps, ces symptômes ne pointaient pas initialement vers une cause spécifique. Intervention: Le patient a été traité par restriction liquidienne, desmopressine SC et divers liquides administrés par voie intraveineuse. L'objectif était d'augmenter la NaS entre 4 et 6 mmol/L/jour et il a requis que la quantité de NaCl et d'eau libre perfusée toutes les heures soit réajustée en permanence. L'accès à l'eau a également dû être restreint, car le patient était incapable de tolérer sa soif. Résultats: Au cours des six premiers jours, la correction atteinte pour la NaS "était" par "a été" d'environ 6 mmol/L/jour. L'état du patient s'est d'abord amélioré, mais à la fin du 6e jour, il a évolué vers une démyélinisation osmotique extrapontine sévère (avec déficits pyramidaux et extrapyramidaux étendus) qui n'a pas répondu à l'administration d'IVIG ni à la diminution de la NaS. Un peu plus de trois semaines plus tard, le patient a présenté une hypotension et a développé un état subfébrile qui se sont révélés secondaires à une maladie d'Addison sévère. Le déséquilibre hydrique et la soif insatiable se sont résorbés progressivement après le remplacement des hormones déficientes, mais les le désordre neurologique est devenu permanent et très invalidant. Enseignements tirés: 1) L'hyponatémie très grave devrait toujours être traitée comme une urgence et surveillée de façon continue en raison de son potentiel à causer des dommages irréversibles. 2) Parce qu'elle est un facteur de risque majeur pour la démyélinisation osmotique, l'hyponatrémie devrait probablement être corrigée à un taux inférieur à 4 mmol/L/jour, surtout si elle est jugée extrême, chronique ou de durée inconnue. 3) L'hyponatrémie peut être un symptôme inaugural de la maladie d'Addison.

16.
J Mol Med (Berl) ; 100(2): 269-284, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34714369

RESUMO

Atypical hemolytic uremic syndrome (aHUS) and C3 glomerulopathy (C3G) have been linked to mutations in many of the proteins that are involved in alternative complement pathway activation. Age and etiology confounded, the prevalence of such mutations has been reported to be over 30 to 50% in these diseases. However, the cohorts studied included many children or individuals with a familial history of complement-related disorders and genetic tests were usually limited to exome sequencing of known causative or risk-associated genes. In this study, a retrospective adult cohort of 35 patients with biopsy-proven thrombotic microangiopathy (the largest in Canada) and 10 patients with C3 glomerulopathy was tested through an extended exome panel to identify causative defects in associated or candidate genes including those of the alternative and terminal complement pathways. A variant of unknown significance was also analyzed for pathogenicity through in vitro studies. To our surprise, the prevalence of known causative or risk-associated variants in either of these cohorts was found to be less than ~ 15% overall. However, the panel used and analyses carried out allowed to identify novel variants of potential clinical significance and a number of candidate genes. The prevalence of known genetic defects in adult-onset aHUS and C3G is thus probably much lower than 30 to 50%. Our results also point towards the importance of investigating diseases of the alternative complement pathway through extended exome panels and in vitro analyses. KEY MESSAGES: The alternative complement pathway plays a major role in the pathogenesis of hemolytic uremic syndrome and C3 glomerulopathy. Based on previous studies, both disorders have been commonly linked to variants in the various intermediates that sustain or regulate this pathway. The prevalence of such mutations in the adult-onset and sporadic forms of these diseases is probably much lower than expected based on larger series. The sporadic forms of complementopathies are likely to involve additional genes that are yet to be uncovered.


Assuntos
Síndrome Hemolítico-Urêmica Atípica/genética , Glomerulonefrite/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Síndrome Hemolítico-Urêmica Atípica/diagnóstico , Biópsia , Complemento C3 , Feminino , Glomerulonefrite/diagnóstico , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Adulto Jovem
17.
Sci Adv ; 8(49): eade7823, 2022 12 09.
Artigo em Inglês | MEDLINE | ID: mdl-36490341

RESUMO

PIK3CA-related overgrowth syndrome (PROS) is a genetic disorder caused by somatic mosaic gain-of-function mutations of PIK3CA. Clinical presentation of patients is diverse and associated with endocrine disruption. Adipose tissue is frequently involved, but its role in disease development and progression has not been elucidated. Here, we created a mouse model of PIK3CA-related adipose tissue overgrowth that recapitulates patient phenotype. We demonstrate that PIK3CA mutation leads to GLUT4 membrane accumulation with a negative feedback loop on insulin secretion, a burst of liver IGFBP1 synthesis with IGF-1 sequestration, and low circulating levels. Mouse phenotype was mainly driven through AKT2. We also observed that PIK3CA mutation induces metabolic reprogramming with Warburg-like effect and protein and lipid synthesis, hallmarks of cancer cells, in vitro, in vivo, and in patients. We lastly show that alpelisib is efficient at preventing and improving PIK3CA-adipose tissue overgrowth and reversing metabolomic anomalies in both animal models and patients.


Assuntos
Tecido Adiposo , Classe I de Fosfatidilinositol 3-Quinases , Mutação com Ganho de Função , Animais , Camundongos , Tecido Adiposo/metabolismo , Classe I de Fosfatidilinositol 3-Quinases/genética , Classe I de Fosfatidilinositol 3-Quinases/metabolismo , Mutação com Ganho de Função/genética , Mutação , Fenótipo
18.
Compr Physiol ; 12(1): 3119-3139, 2021 12 29.
Artigo em Inglês | MEDLINE | ID: mdl-34964111

RESUMO

The loop of Henle plays a variety of important physiological roles through the concerted actions of ion transport systems in both its apical and basolateral membranes. It is involved most notably in extracellular fluid volume and blood pressure regulation as well as Ca2+ , Mg2+ , and acid-base homeostasis because of its ability to reclaim a large fraction of the ultrafiltered solute load. This nephron segment is also involved in urinary concentration by energizing several of the steps that are required to generate a gradient of increasing osmolality from cortex to medulla. Another important role of the loop of Henle is to sustain a process known as tubuloglomerular feedback through the presence of specialized renal tubular cells that lie next to the juxtaglomerular arterioles. This article aims at describing these physiological roles and at discussing a number of the molecular mechanisms involved. It will also report on novel findings and uncertainties regarding the realization of certain processes and on the pathophysiological consequences of perturbed salt handling by the thick ascending limb of the loop of Henle. Since its discovery 150 years ago, the loop of Henle has remained in the spotlight and is now generating further interest because of its role in the renal-sparing effect of SGLT2 inhibitors. © 2022 American Physiological Society. Compr Physiol 12:1-21, 2022.


Assuntos
Túbulos Renais , Alça do Néfron , Humanos , Rim , Néfrons , Cloreto de Sódio
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