Mouse model of type II Bartter's syndrome. II. Altered expression of renal sodium- and water-transporting proteins.
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.
Wagner
Carsten A
CA
Institute of Physiology, Center for Integrative Human Physiology, Univ. of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland. Wagnerca@access.uzh.chand
Loffing-Cueni
Dominique
D
Yan
Qingshang
Q
Schulz
Nicole
N
Fakitsas
Panagiotis
P
Carrel
Monique
M
Wang
Tong
T
Verrey
Francois
F
Geibel
John P
JP
Giebisch
Gerhard
G
Hebert
Steven C
SC
Loffing
Johannes
J
D000222:Adaptation, Physiological / Q000502:physiology; D000818:Animals; D001477:Bartter Syndrome / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D027682:Cation Transport Proteins / Q000235:genetics / Q000378:metabolism; D015232:Dinoprostone / Q000097:blood; D004195:Disease Models, Animal; D053503:Epithelial Sodium Channels / Q000235:genetics / Q000378:metabolism; D007686:Kidney Tubules, Distal / Q000378:metabolism; D007687:Kidney Tubules, Proximal / Q000378:metabolism; D008138:Loop of Henle / Q000378:metabolism*; D051379:Mice; D008817:Mice, Mutant Strains; D024661:Potassium Channels, Inwardly Rectifying / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012964:Sodium / Q000378:metabolism*; D000074083:Sodium-Hydrogen Exchanger 3; D017923:Sodium-Hydrogen Exchangers / Q000235:genetics / Q000378:metabolism; D050613:Sodium-Phosphate Cotransporter Proteins, Type IIa / Q000235:genetics / Q000378:metabolism; D028021:Sodium-Potassium-Chloride Symporters / Q000235:genetics / Q000378:metabolism; D064466:Solute Carrier Family 12, Member 1; D015854:Up-Regulation / Q000502:physiology; D014867:Water / Q000378:metabolism; D000099236:Solute Carrier Family 11, Member 2
D002352:Carrier Proteins; D027682:Cation Transport Proteins; D015232:Dinoprostone; D053503:Epithelial Sodium Channels; D024661:Potassium Channels, Inwardly Rectifying; D012964:Sodium; D000074083:Sodium-Hydrogen Exchanger 3; D017923:Sodium-Hydrogen Exchangers; D050613:Sodium-Phosphate Cotransporter Proteins, Type IIa; D028021:Sodium-Potassium-Chloride Symporters; D064466:Solute Carrier Family 12, Member 1; D014867:Water; D000099236:Solute Carrier Family 11, Member 2; C510693:Kcnj1 protein, mouse; C578714:SLC12A1 protein, human; C000613385:SLC9A3 protein, human; C578715:Slc12a1 protein, mouse; C493555:Slc34a1 protein, mouse; C000613386:Slc9a3 protein, mouse