Mouse model of type II Bartter's syndrome. II. Altered expression of renal sodium- and water-transporting proteins

Am J Physiol Renal Physiol. 2008 Jun;294(6):F1373-80. doi: 10.1152/ajprenal.00613.2007. Epub 2008 Mar 5.


Bartter's syndrome represents a group of hereditary salt- and water-losing renal tubulopathies caused by loss-of-function mutations in proteins mediating or regulating salt transport in the thick ascending limb (TAL) of Henle's loop. Mutations in the ROMK channel cause type II antenatal Bartter's syndrome that presents with maternal polyhydramnios and postnatal life-threatening volume depletion. We have developed a colony of Romk null mice showing a Bartter-like phenotype and with increased survival to adulthood, suggesting the activation of compensatory mechanisms. To test the hypothesis that upregulation of Na(+)-transporting proteins in segments distal to the TAL contributes to compensation, we studied expression of salt-transporting proteins in ROMK-deficient (Romk(-/-)) mice. Plasma aldosterone was 40% higher and urinary PGE(2) excretion was 1.5-fold higher in Romk(-/-) compared with wild-type littermates. Semiquantitative immunoblotting of kidney homogenates revealed decreased abundances of proximal tubule Na(+)/H(+) exchanger (NHE3) and Na(+)-P(i) cotransporter (NaPi-IIa) and TAL-specific Na(+)-K(+)-2Cl(-)-cotransporter (NKCC2/BSC1) in Romk(-/-) mice, while the distal convoluted tubule (DCT)-specific Na(+)-Cl(-) cotransporter (NCC/TSC) was markedly increased. The abundance of the alpha-,beta-, and gamma-subunits of the epithelial Na(+) channel (ENaC) was slightly increased, although only differences for gamma-ENaC reached statistical significance. Morphometry revealed a fourfold increase in the fractional volume of DCT but not of connecting tubule (CNT) and collecting duct (CCD). Consistently, CNT and CD of Romk(-/-) mice revealed no apparent increase in the luminal abundance of the ENaC compared with those of wild-type mice. These data suggest that the loss of ROMK-dependent Na(+) absorption in the TAL is compensated predominately by upregulation of Na(+) transport in downstream DCT cells. These adaptive changes in Romk(-/-) mice may help to limit renal Na(+) loss, and thereby, contribute to survival of these mice.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptation, Physiological / physiology
  • Animals
  • Bartter Syndrome / genetics
  • Bartter Syndrome / metabolism*
  • Bartter Syndrome / physiopathology*
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism*
  • Cation Transport Proteins / genetics
  • Cation Transport Proteins / metabolism
  • Dinoprostone / blood
  • Disease Models, Animal
  • Epithelial Sodium Channels / genetics
  • Epithelial Sodium Channels / metabolism
  • Kidney Tubules, Distal / metabolism
  • Kidney Tubules, Proximal / metabolism
  • Loop of Henle / metabolism*
  • Mice
  • Mice, Mutant Strains
  • Potassium Channels, Inwardly Rectifying / genetics*
  • Potassium Channels, Inwardly Rectifying / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Sodium / metabolism*
  • Sodium-Hydrogen Exchanger 3
  • Sodium-Hydrogen Exchangers / genetics
  • Sodium-Hydrogen Exchangers / metabolism
  • Sodium-Phosphate Cotransporter Proteins, Type IIa / genetics
  • Sodium-Phosphate Cotransporter Proteins, Type IIa / metabolism
  • Sodium-Potassium-Chloride Symporters / genetics
  • Sodium-Potassium-Chloride Symporters / metabolism
  • Solute Carrier Family 12, Member 1
  • Up-Regulation / physiology
  • Water / metabolism


  • Carrier Proteins
  • Cation Transport Proteins
  • Epithelial Sodium Channels
  • Kcnj1 protein, mouse
  • Potassium Channels, Inwardly Rectifying
  • SLC12A1 protein, human
  • SLC9A3 protein, human
  • Slc12a1 protein, mouse
  • Slc34a1 protein, mouse
  • Slc9a3 protein, mouse
  • Sodium-Hydrogen Exchanger 3
  • Sodium-Hydrogen Exchangers
  • Sodium-Phosphate Cotransporter Proteins, Type IIa
  • Sodium-Potassium-Chloride Symporters
  • Solute Carrier Family 12, Member 1
  • solute carrier family 11- (proton-coupled divalent metal ion transporters), member 2
  • Water
  • Sodium
  • Dinoprostone