Hereditary disorders of magnesium reveal new proteins implicated in its renal transport
Trastornos hereditarios del magnesio revelan nuevas proteínas comprometidas en su transporte renal.
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Complicaciones en su inserción." ] ] "contieneResumen" => array:2 [ "es" => true "en" => true ] "contieneTextoCompleto" => array:1 [ "en" => true ] "contienePdf" => array:1 [ "en" => true ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Pilar Royo, Alicia García-Testal, Amparo Soldevila, Joaquín Panadero, Jose Miguel Cruz" "autores" => array:5 [ 0 => array:2 [ "nombre" => "Pilar" "apellidos" => "Royo" ] 1 => array:2 [ "nombre" => "Alicia" "apellidos" => "García-Testal" ] 2 => array:2 [ "nombre" => "Amparo" "apellidos" => "Soldevila" ] 3 => array:2 [ "nombre" => "Joaquín" "apellidos" => "Panadero" ] 4 => array:2 [ "nombre" => "Jose Miguel" "apellidos" => "Cruz" ] ] ] ] ] "idiomaDefecto" => "en" "Traduccion" => array:1 [ "es" => array:9 [ "pii" => "X0211699508003998" "doi" => " " "estado" => "S300" "subdocumento" => "" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:1 [ "total" => 0 ] "idiomaDefecto" => "es" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/X0211699508003998?idApp=UINPBA000064" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/X2013251408003995?idApp=UINPBA000064" "url" => "/20132514/0000002800000005/v0_201502091635/X2013251408003995/v0_201502091635/en/main.assets" ] "en" => array:12 [ "idiomaDefecto" => true "titulo" => "Hereditary disorders of magnesium reveal new proteins implicated in its renal transport" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "549" "paginaFinal" => "553" ] ] "autores" => array:1 [ 0 => array:3 [ "autoresLista" => "Armando Luis Negri" "autores" => array:1 [ 0 => array:4 [ "nombre" => "Armando Luis" "apellidos" => "Negri" "email" => array:1 [ 0 => "negri@casasco.com.ar" ] "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "affa" ] ] ] ] "afiliaciones" => array:1 [ 0 => array:3 [ "entidad" => "Instituto de Investigaciones Metabólicas, Universidad del Salvador, Buenos Aires, Buenos Aires, Argentina, " "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "affa" ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Trastornos hereditarios del magnesio revelan nuevas proteínas comprometidas en su transporte renal." ] ] "textoCompleto" => "INTRODUCTION <br></br><br></br>Magnesium is the second most common intracellular ion and the fourth most abundant cation in the body. This divalent cation plays an essential role in many metabolic processes such as protein and DNA synthesis and oxidative phosphorylation. It is also a critical cofactor in a high number of enzymatic reactions, and is involved in regulation of ion channels.1 In normal subjects, an acute change in serum magnesium levels affects  parathyroid  function:  decreased  magnesium  levels stimulate secretion, while hypermagnesemia inhibits PTH release.2,3 <br></br><br></br>Magnesium  deficiency  therefore  affects  multiple  body functions. Symptoms of magnesium deficiency mainly consist of neuromuscular hyperexcitability ranging from latent to overt tetany and/or seizures,4 and from simple electrocardiographic changes  including prolonged PR and QT intervals to complex cardiac arrhythmia. Magnesium deficiency is a very common problem, found in more than 10% of hospitalized patients, and may occur  in up  to 65% of patients in intensive therapy units.5 A complication seen in adult patients with  chronic hypomagnesemia  is  chondrocalcinosis, particularly in the knees, that may lead to joint function impairment.4 <br></br><br></br>Magnesium  deficiency  usually  results  from  magnesium loss, either through the gastrointestinal tract or the kidney. Diseases causing acute or chronic diarrhea, either or not associated  to  malabsorption,  commonly  induce  magnesium  deficiency.  Diabetes  is  probably  the  most  common  systemic disease associated to hypomagnesemia. Osmotic diuresis due to  glycosuria  results  in  renal  loss  of magnesium. Different drugs  such  as  diuretics,  aminoglycosides,6 cyclosporin,7 and cisplatin may also cause renal loss of magnesium. <br></br><br></br>RENAL HANDLING OF MAGNESIUM  HOMEOSTASIS <br></br><br></br>Magnesium  plasma  levels  are  regulated within  a  very  narrow margin by changes in urinary excretion of this cation in response to intestinal absorption changes. The kidney therefore  plays  an  essential  role  in  magnesium  homeostasis.4,8 Only  a  small  fraction  of  filtered magnesium  is  reabsorbed into the proximal tubule (approximately 15% of the filtered load). Most  renal  reabsorption of magnesium occurs  in  the thick ascending limb of Henle¿s loop (± 70%) through a paracellular passive transport (fig. 1) driven by an electric gradient. Approximately 10% of filtered magnesium is reabsorbed  into  the  distal  convoluted  tubule  (DCT)  and  the <br></br>connecting tubule by a process of transcellular active transport.6,8 Apical entry into DCT and connecting tubule cells is mediated by  special magnesium-permeable channels called TRPM6  (transient receptor  potential  cation  channel,  subfamily M, member  6)  that  are  driven  by  a  favorable  transmembrane voltage gradient.9 The mechanism of basolateral magnesium  exit  to  the  interstitium  is  unknown  (fig.  2). Magnesium should be extruded against an unfavorable electrochemical gradient, which is most likely to occur through a Na+/Mg2+ exchanger and/or a Mg2+ATPase. Finally, 3%-5% of filtered magnesium is excreted in urine. In hypomagnesemia  states,  the kidney may  reduce magnesium excretion  to 0.5% of the filtered load, while in hypermagnesemia it may excrete up  to 80% of  the  filtered  load. Despite  the  significant  role  play  by  transepithelial  transport  mechanisms  in magnesium handling, such mechanisms have not been fully elucidated yet. <br></br><br></br>HEREDITARY DISORDERS OF MAGNESIUM HANDLING AND NEW PROTEINS IMPLICATED IN MAGNESIUM TRANSPORT <br></br><br></br>Hereditary primary hypomagnesemia is a rare group of heterogeneous  disorders  characterized  by  renal  or  intestinal magnesium loss with magnesium depletion frequently associated  to  impaired  calcium  excretion,  resulting  in  shared symptoms  of  tetany  and  generalized  seizures.  Study  of these disorders has  allowed  for  a deeper understanding of the cellular and molecular mechanisms  that play a significant role in renal magnesium reabsorption. In recent years, genetic  studies  on  several  of  these  hereditary  disorders have  revealed  four new proteins  that are  involved  in  renal magnesium transport: 1) claudin-16, 2) the abovementioned magnesium  epithelial  channel, TRPM6, 3)  the gamma  subunit  of  Na,K-ATPase,  and  4)  pro-EGF  (pro-epidermal growth factor). <br></br><br></br>Familial hypomagnesemia with hypercalciuria and nephrocalcinosis and mutations in tight junction proteins claudin-16 and -19 <br></br>In 1999, a rare syndrome, familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC), was found to be caused by mutation of paracellin-1, subsequently called claudin-16.10 Tubular  disorders  and  progression  to  renal  insufficiency  are  usually  resistant  to magnesium  replacement  and hydrochlorothiazide treatment, but magnesemia may improve with the advance of renal failure. <br></br><br></br>As previously stated, the bulk of magnesium tubular reabsorption occurs in the ascending thick limb of Henle¿s loop. <br></br>This  tubular  segment  consists  of  a  watertight  epithelium, which is very important to generate the medullary hyperosmolarity gradient caused by sodium chloride absorption on which subsequent water reabsorption by the collecting tubule depends.  Sodium  chloride  reabsorption  depends  on  the presence in the apical membrane of tubular cells in this region of an electron-neutral cotransporter carrying two chlorines,  one  potassium,  and  one  sodium  (NKCC2), which  is the molecular  target of  the  so-called  loop diuretics  such as furosemide.  Potassium  must  exit  again  into  the  tubular lumen  through  special  channels  called ROMK  (renal outer medullary K channels). This generates and maintains a positive  intratubular  potential  of  6  to  12 mVolt, which  in  turn drives paracellular reabsorption of divalent cations calcium and magnesium.   The  finding  that  the  paracellular  protein <br></br>claudin-16, expressed in the tight junctions of the ascending thick limb of Henle¿s loop, was involved in magnesium reabsorption  initially suggested  that  this protein could be  the paracellular  route  for magnesium  reabsorption. When a series of claudin-16 mutations found in FHHNC patients were investigated by expressing them in renal cell lines, most of these mutated proteins were found to be retained within the cell. A few mutant proteins were directed, as normally occurs,  towards  tight  junctions,  but  these  showed  a  reduced conductivity  for magnesium.11 It was  therefore  thought  that claudin-16 mutations found in FHHNC affected its intracellular traffic or paracellular permeability to magnesium. However, other studies have shown that claudin-16 only has a low permeability to magnesium, but has a high permeability to  sodium,  and  it was  postulated  that  claudin-16  formed  a paracellular shunt for sodium in the interstitium to return to the tubular lumen, contributing to the generation of the positive potential in the tubular lumen.12 This hypothesis was recently evaluated using RNA interference  technology  to generate a mouse model with a great  reduction  in claudin-16 expression.13 This mouse model showed urinary loss of magnesium  and  calcium, bone mass  reduction,  and  subsequent <br></br>development  of  nephrocalcinosis  as  seen  in  patients  with FHHNC. A detailed  analysis  of  the  function  of  the  ascending  thick  limb of Henle  in  these mice with no claudin-16 showed  a  decreased  paracellular  permeability  to  sodium with  a  strong  reduction  in  the  lumen-positive  potential. These data would  show  that claudin-16 may be part of  the tight junction complex that selectively mediates back diffusion of sodium from interstitium to the lumen of the ascending  thick  limb of Henle, generating  the electropositive  luminal potential  that  is critical  for paracellular  reabsorption of calcium and magnesium. <br></br><br></br>In a study on patients with mutations resulting in a complete loss of function of both claudin-16 alleles, they were found to be younger at symptom start as compared to subjects who had  an  allele  providing  a  partial  function.14 In  addition,  patients with a complete  function  loss had a  faster  impairment of glomerular filtration rate, which caused that more than half of them required renal replacement therapy at 15 years of age, As compared to only 20% of those with residual allele function. Existence of residual claudin-16 function could therefore delay progression to renal failure in patients with FHHNC. <br></br><br></br>More recently, nine families with severe hypomagnesemia with mutations in the gene encoding claudin-19 have been reported.15 Claudin-19  is another  tight  junction protein expressed in renal tubules and eyes.16 This is why patients with claudin-19 mutations have ocular symptoms such as severe visual impairment,  macular  coloboma,  horizontal  nystagmus,  and marked myopia which do not occur in patients with claudin16 mutations.  In  epithelial  cells  of  pig  kidneys,  claudin-19 acts as a chloride blocker, while claudin-16 acts as a sodium channel.  Claudin-19  mutations  found  in  patients  with FHHNC were unable  to block permeability  to chloride. Co-expression of claudin-16 and -19 generates cation selectivity of the tight junction in a synergistic manner.17 <br></br><br></br>Hypomagnesemia with secondary hypocalcemia and mutations of the magnesium channel TRPM6 <br></br>This  rare  autosomal  recessive  disease  (HSH;  OMIM 602014),  characterized  by  low  serum  magnesium  levels with  a  high  urinary  fractional  secretion  of magnesium,  is caused  by  nonsense  or  antisense  mutations  in  the  apical magnesium  channel, TRPM6.18 Subsequent  studies  showed TRPM6 to be a channel permeable to magnesium expressed in  the  luminal membrane of  intestinal epithelium and DCT and  connecting  tubule.19 TRPM6  inactivating  mutations cause  an  intestinal  absorption  impairment  combined  with renal loss of the cation. <br></br><br></br>Gitelman syndrome is another hereditary disorder also causing changes in the epithelial magnesium channel. This hereditary disorder is caused by function loss due to mutations in the gene encoding  the Na-Cl cotransporter of  the distal convoluted  tubule  (NCCT).  It  is  characterize  by  hypokalemia, metabolic  alkalosis,  hypomagnesemia,  and  hypocalciuria. Hypomagnesemia  developing  during  chronic  hydrochlorothiazide treatment and in Na-Cl cotransporter knockout mice, an animal model of Gitelman syndrome, is due to downregulation of the epithelial magnesium channel, TRPM6. Downregulation of this channel may therefore represent a general mechanism  involved  in  the  pathogenesis  of  hypomagnesemia that is associated to inhibition or inactivation of the Na-Cl co-transporter.20,21 <br></br><br></br>Autosomal dominant renal hypomagnesemia with hypocalciuria and mutations in the Na,K-ATPase subunit <br></br>In  the  kidney, Na+, K+-ATPase  is  an  oligomer  (alpha/beta/gamma) with equimolar amounts of the alpha and beta essential subunits and a small hydrophobic protein, the gamma subunit. FXYD2 or gamma subunit of Na,K-ATPase belongs to the FXYD  family  of  proteins, which  are  tissue-specific Na, K-ATPase  modulators  and  include  phospholemman  (or FXYD1)  and  CHIF  (corticosteroid  hormone-induced  factor or FXYD4 ). Expression of protein FXYD2 or gamma subunit is essentially restricted to the kidney and has two main variants,  gamma  a  and  gamma  b. While  phospholemman  and CHIF increase the apparent affinity of Na, K-ATPase for intracellular Na(+),  the gamma subunit decreases sodium affinity.22 The  two variants of  the gamma  subunit affect  the catalytic properties of the pump. Both variants are coexpressed in the proximal tubule and medullary portion of the ascending thick limb of Henle¿s loop. Distribution of both variants in all other  tubular  segments differs: only  the gamma  a variant  is present in macula densa and principal cells of the initial parts of the collecting tubule. The gamma b variant is in the cortical portion  of  the  ascending  thick  limb  of  Henle¿s  loop.23 The gamma subunit is an activator of Na+, K+-ATPase in the external medullary zone of the kidney, and its phosphorylation by  PKA increases  its  capacity  to  stimulate  hydrolysis  of ATP.24 <br></br><br></br>In a large Dutch family with autosomal dominant renal hypomagnesemia associated to hypercalciuria, the disease locus was  recently  mapped  to  a  5.6-cM  region  on  chromosome 11q23.25 After candidate  screening, a heterozygous mutation was identified in gene FXYD2, encoding for the gamma subunit  of  Na(+),K(+)-ATPase,  cosegregating  with  patients from this family, and which was not found in 132 control chromosomes. The mutation leads to a G41R substitution, introducing a charged amino acid residue into the predicted transmembrane  region of  the gamma subunit protein. Expression studies  in  insect  Sf9  and  COS-1  cells  showed  the  mutant gamma subunit to be misrouted and to accumulate in perinuclear structures.    In addition  to misrouting of mutant G41R, <br></br>Western  blot  analysis  of Xenopus  oocytes  expressing  either the wild or the mutant type of the gamma subunit showed that a post-translational change was lacking in the mutant gamma subunit. Finally, researchers studied two subjects who lacked a copy of the FXYD2 gene and found that the serum magnesium levels  were  within  the  normal  range.  Retention  of  mutant gamma subunits in precise intracellular structures was therefore  associated  to  an  aberrant  post-translational  processing. Thus, the G41R mutation in protein FXYD2 causes dominant renal hypomagnesemia associated  to hypocalciuria  through a negative dominant mechanism. Despite the foregoing, the mechanism by which  a mutation  in  a  regulatory protein of  the Na(+),K(+)-ATPase  pump  causes  renal magnesium  loss  has not been elucidated yet. <br></br><br></br>Isolated recessive renal hypomagnesemia and mutations in pro-EGF <br></br>This disease  (IRH)  is  characterized by  low magnesium  levels, normocalciuria,  and mental  retardation with  seizures. Groenestetege et al studied  two sisters born from asymptomatic inbred parents, which suggested an autosomal recessive pattern.26 Mutations  in other genes previously  identified with  renal  handling  of magnesium were  ruled  out  in  these patients. Genetic mapping allowed these authors to identify a critical gap junction with a LOD score of 2.66 at 18.4 cM on chromosome 4 between markers D4S2623 and D4S1575. Among  candidate  genes  located  in  that  region,  the  EGF (epidermal growth factor) gene was considered highly relevant. EGF  sequencing  in  affected  subjects  identified  a  homozygous mutation C3209T in exon 22  that caused substitution  of  a  highly  conserved  proline  by  a  leucine  in  the cytoplasmic tail of pro-EGF (P1070L). The EGF gene consists of 24 exons encoding a long precursor protein anchored to the type I membrane that undergoes proteolytic cleavage to be converted into pro-EGF, which eventually generates an acidic 53-amino  acid hormone, EGF.27 EGF belongs  to  the EGF-like  growth  factor  family, whose members  have  profound effects upon cell differentiation, and is a potent mitogen.28 EGF is bound with great affinity to the EGF receptor (EGFR). EGF  is very abundant  in  the DCT and appears  to be  secreted  both  to  the  apical  and  basolateral  sides, while EGFR mainly occurs in the basolateral membrane. Groenestege et al26 showed that the P1070L mutation in pro-EGF appeared to affect EGF routing and basolateral secretion, whereas apical release was not affected in Madin-Darby canine kidney  cells  (MDCK). Despite  the  fact  that  proline  1,070 may be part of  the PXXP motif causing basolateral sorting of  pro-EGF,  expression  of  mutated  pro-EGF  (P1070L)  in human embryonic kidney cells (HEK) may also affect EGF <br></br>formation, suggesting  the possibility  that  the mutation may affect pro-EGF processing. <br></br><br></br>Regardless of whether the mutation found in patients with IRH  causes mistargeting  or  impairment  in  pro-EGF  processing, Groenestege et al26 found  that EGF markedly  increases the activity of  the magnesium channel TRPM6. This  led  the authors to propose a physiological model in which a basal activity  of  basolateral  activation  of  EGFR  is  required  for TRPM6 activity and apical entry of magnesium. This model is  consistent  with  the  hypomagnesemia  seen  in  cancer  patients  treated with  the  anti-EGF  antibody  cetuximab.29,30 To support this concept, the authors showed that cetuximab also antagonized stimulation of TRPM6 activity by EGF in cultured cells. <br></br><br></br>PERSPECTIVE <br></br><br></br>After many  decades  of  research,  in-depth  understanding  of control of magnesium homeostasis  is  still  lacking. Study of the different hereditary disorders of magnesium has demonstrated new proteins involved in its handling. The most significant finding may perhaps be that EGF acts as an autocrine/paracrine  mangesiotropic  factor, which  opens  the  way  to  a better understanding of active magnesium reabsorption in the distal tubule. Pending questions include whether the effect of EGF  is  exerted  through  regulation  of  channel  activity  or whether it regulates its apical expression, and which are its intracellular signaling pathways. Understanding of all these mechanisms will open the door to a set of therapeutic objectives to be able to manipulate renal magnesium handling. <br></br>" "pdfFichero" => "P-E-S-A362-EN.pdf" "tienePdf" => true "tieneResumen" => true "resumen" => array:2 [ "es" => array:1 [ "resumen" => "El magnesio es el segundo ión intracelular más común y el cuarto catión más abundante del cuerpo. Este catión bivalente tiene un rol fundamental en numerosos procesos metabólicos como la síntesis de proteínas y ADN y la fosforilación oxidativa; es también un cofactor crítico de gran número de reacciones enzimáticas, e interviene en la regulación de canales iónicos (1). En los sujetos normales, un cambio agudo en la concentración sérica de magnesio afecta la función paratiroidea: su caída estimula la secreción, mientras que la hipermagnesemia inhibe la liberación de PTH (2,3)." ] "en" => array:1 [ "resumen" => "Magnesium is the second most common intracellular ion and the fourth most abundant cation in the body. This divalent cation plays an essential role in many metabolic processes such as protein and DNA synthesis and oxidative phosphorylation. It is also a critical cofactor in a high number of enzymatic reactions, and is involved in regulation of ion channels.1 In normal subjects, an acute change in serum magnesium levels affects parathyroid function: decreased magnesium levels stimulate secretion, while hypermagnesemia inhibits PTH release.2,3" ] ] "bibliografia" => array:2 [ "titulo" => "Bibliography" "seccion" => array:1 [ 0 => array:1 [ "bibliografiaReferencia" => array:29 [ 0 => array:3 [ "identificador" => "bib1" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "1-Naderi AS, Reilly RF jr: Hereditary etiologies of hypomagnesemia. Nat Clin Pract Nephrol 2008; 4(2) 80-89." "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 1 => array:3 [ "identificador" => "bib2" "etiqueta" => "2" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "2- Ferment O., Garnier P.E., Touitou Y. Comparison of the feedback effect of magnesium and calcium on parathyroid hormone secretion in man. J Endocrinol 1987; 113:117¿122." "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 2 => array:3 [ "identificador" => "bib3" "etiqueta" => "3" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "3- Cholst I.N., et al. The influence of hypermagnesemia on serum calcium and parathyroid hormone levels in human subjects. N Engl J Med 1984; 310:1221¿1225." "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 3 => array:3 [ "identificador" => "bib4" "etiqueta" => "4" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "4- Konrad M., Schlingmann K.P., Gudermann T. Insights into the molecular nature of magnesium homeostasis. Am. J Physiol Renal Physiol 2004; 286:F599¿F605." 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"contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] ] ] ] ] ] "idiomaDefecto" => "en" "url" => "/20132514/0000002800000005/v0_201502091635/X2013251408004006/v0_201502091635/en/main.assets" "Apartado" => null "PDF" => "https://static.elsevier.es/multimedia/20132514/0000002800000005/v0_201502091635/X2013251408004006/v0_201502091635/en/P-E-S-A362-EN.pdf?idApp=UINPBA000064&text.app=https://revistanefrologia.com/" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/X2013251408004006?idApp=UINPBA000064" ]
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