Nucleotide Sequence of the Na+/H+ Exchanger-8 in Patients With Congenital Sodium Diarrhea

Department of Pediatrics, Mattel Children's Hospital, David Geffen School of Medicine at the University of California, Los Angeles, USA.
Journal of pediatric gastroenterology and nutrition (Impact Factor: 2.63). 06/2011; 53(5):474-7. DOI: 10.1097/MPG.0b013e318227ad6e
Source: PubMed


Sodium absorption by the intestine is mediated by brush border Na/H exchangers, which include the NHE3 and NHE8 isoforms. We demonstrated a maturational decrease in NHE8 and increase in NHE3 in mouse intestine mRNA abundance and brush border membrane protein abundance, indicating a developmental switch of isoforms. Congenital sodium diarrhea is a rare autosomal recessive disorder characterized by polyhydramnios, hyponatremia, metabolic acidosis, and diarrhea with a high sodium content. Previous studies using intestinal brush border membrane vesicles from patients with this disorder have demonstrated a decrease in Na/H exchanger activity. Because some patients with congenital sodium diarrhea improve with age and knowing the developmental switch from NHE8 to NHE3, NHE8 may be a candidate gene for this disorder. We sequenced NHE8 from 5 patients with this disorder and found no disease-causing homozygous mutations. Although brush border membrane Na/H exchange activity may be decreased, exonic mutations in NHE8 cannot account for this disorder in these subjects.

Download full-text


Available from: Orson W Moe, Oct 01, 2015
24 Reads
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: In recent years, the field of intestinal physiology has witnessed significant progress in our understanding of the expression and function of ion transport proteins and their genes under physiological and pathophysiological conditions. This review will present some of these most recent advances in the small intestinal ion transport mechanisms. One of the new and exciting aspects of this field has been the integration of function and structure of several intestinal transport processes. This is well exemplified by the discussed intricacies of intestinal bicarbonate secretion as well as the role of scaffolding PDZ proteins interacting with several transporters. We also discuss some of the most recent data pointing to the role of ion transporters in the pathogenesis of inflammation-associated diarrhea and their potential role in the maintenance of epithelial integrity. Mouse models deficient in some of the key genes encoding ion transporters and their adapter proteins continue to provide important clues into intestinal transport processes. Several of the new in-vivo findings revise or complement past paradigms, many of which were derived from in-vitro approaches. New data on the interdependent functions of multiple transporters, as exemplified here by intestinal bicarbonate secretion, increase the complexity of the intestinal ion transport mechanisms and continue to contribute to a more integrated view of the transport phenomena in the gut. Data from patients and mouse models of intestinal inflammation also increase our understanding of the pathophysiology of inflammation-associated diarrhea.
    Current opinion in gastroenterology 04/2009; 25(2):87-91. DOI:10.1097/MOG.0b013e3283260900 · 4.29 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: In this review, we focus on the recent (March 2010 to September 2011) advances in small intestinal ion transport, with particular emphasis on sodium, chloride, bicarbonate, and calcium transport mechanisms under physiological and pathophysiological conditions. Knockout of NHERF1 and NHERF2 allowed translation of the data largely derived from the in-vitro models into a living organism. These studies also expand our knowledge about the complexity of intestinal transporter interactomes, define the role for scaffolding proteins in basal and regulated apical transport, and help identify potential targets for pharmacological approaches. We continue to accumulate novel information about the function and regulation of NHE3 (including its role in regulating paracellular Ca2+ flux), NHE8, as well as about the complexity of the intestinal Cl- and HCO3- transport in health and disease. Thanks to the new genetically engineered mouse models, a significant progress has been made in our understanding of the role of NHERF proteins in regulation of intestinal Na+ absorption. Significant novel data on the coordinated function of bicarbonate, chloride, and sodium transporters contributes to our current views of the integrative physiology of the small intestinal electrolyte transport.
    Current opinion in gastroenterology 12/2011; 28(2):130-4. DOI:10.1097/MOG.0b013e32834e7bc3 · 4.29 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The Na(+)/H(+) exchanger-3 (NHE3) belongs to the mammalian NHE protein family and catalyzes the electro-neutral exchange of extracellular sodium for intracellular proton across cellular membranes. Its transport function is of essential importance for the maintenance of the body's salt and water homeostasis as well as acid-base balance. Indeed, NHE3 activity is finely regulated by a variety of stimuli, both acutely and chronically, and its transport function is fundamental for a multiplicity of severe and world-wide infection-pathological conditions. This review aims to provide a concise overview of NHE3 physiology and discusses the role of NHE3 in clinical conditions of prominent importance, specifically in hypertension, diabetic nephropathy, heart failure, acute kidney injury, and diarrhea. Study of NHE3 function in models of these diseases has contributed to the deciphering of mechanisms that control the delicate ion balance disrupted in these disorders. The majority of the findings indicate that NHE3 transport function is activated before the onset of hypertension and inhibited thereafter; NHE3 transport function is also upregulated in diabetic nephropathy and heart failure, while it is reported to be downregulated in acute kidney injury and in diarrhea. The molecular mechanisms activated during these pathological conditions to regulate NHE3 transport function are examined with the aim of linking NHE3 dysfunction to the analyzed clinical disorders.
    AJP Cell Physiology 03/2012; 302(11):C1569-87. DOI:10.1152/ajpcell.00017.2012 · 3.78 Impact Factor
Show more