Identification of molecules

Fumiaki Ando
Tokyo Medical and Dental University, Tokyo, Japan

Water and sodium homeostasis are closely interrelated and precisely regulated by the kidneys. The disruption of homeostatic balance is a common problem encountered in clinical practice. Water channels and amiloride-sensitive epithelial Na+ channel (ENaC) are representative molecules to determine body fluid-electrolyte parameters in blood and urine.

The first water channel, aquaporin-1 (AQP1), was identified as a 28-kDa membrane protein (CHIP28) in erythrocytes by Peter Agre and coworkers (1). Agre was awarded the 2003 Nobel Prize in Chemistry for this discovery. AQP1 is a constitutively open water channel present at the luminal membrane of the proximal tubule cells and the descending thin limbs of the loop of Henle in the kidney. AQP2 is another important aquaporin localized in the renal collecting ducts (CD) that is critical in regulating urine volume (2). In contrast to AQP1, AQP2 is dynamically regulated and is translocated from intracellular vesicles to the apical plasma membrane in response to dehydration leading to water reabsorption from urine via the luminal AQP2. Loss-of-function mutations in the AQP2 cause congenital nephrogenic diabetes insipidus.

ENaC is a plasma membrane protein localized primarily in the renal CD that plays a fundamental role in sodium reabsorption and regulates body sodium content and blood pressure. Canessa et al. found the first ENaC subunit (α), cloned from the colon of salt-deprived rats, in 1993 (3). Two other subunits (β and γ) were identified by functional complementation of the α subunit (4). Liddle syndrome is caused by gain-of-function mutations in the ENaC that induce impairment of its degradation by the ubiquitin-proteasome system and a subsequent increase in ENaC expression.


  1. Preston GM, Carroll TP, Guggino WB, Agre P. Appearance of water channels in Xenopus oocytes expressing red cell CHIP28 protein. Science. 1992;256(5055):385-7.
  2. Fushimi K, Uchida S, Hara Y, Hirata Y, Marumo F, Sasaki S. Cloning and expression of apical membrane water channel of rat kidney collecting tubule. Nature. 1993;361(6412):549-52.
  3. Canessa CM, Horisberger JD, Rossier BC. Epithelial sodium channel related to proteins involved in neurodegeneration. Nature. 1993;361(6411):467-70.
  4. Canessa CM, Schild L, Buell G, Thorens B, Gautschi I, Horisberger JD, Rossier BC. Amiloride-sensitive epithelial Na+ channel is made of three homologous subunits. Nature. 1994;367(6462):463-7.

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