Mouse model of type II Bartter's syndrome. I. Upregulation of thiazide-sensitive Na-Cl cotransport activity.
ROMK-deficient (Romk(-/-)) mice exhibit polyuria, natriuresis, and kaliuresis similar to individuals with type II Bartter's form of hyperprostaglandin E syndrome (HPS; antenatal Bartter's syndrome). In the present study, we utilized both metabolic and clearance studies to define the contributions of specific distal nephron segments to the renal salt wasting in these mice. The effects of furosemide, hydrochlorothiazide, and benzamil on urinary Na(+) and K(+) excretion in both wild-type (Romk(+/+)) and Romk(-/-) mice were used to assess and compare salt transport by the Na(+)-K(+)-2Cl(-) cotransporter (NKCC2)-expressing thick ascending limb (TAL), the Na(+)-Cl(-) cotransporter (NCC)-expressing distal convoluted tubule (DCT1/DCT2), and the epithelial Na(+) channel (ENaC)-expressing connecting segment (CNT) and collecting duct (CD), respectively. Whole kidney glomerular filtration rate was reduced by 47% in Romk(-/-) mice. Furosemide-induced increments in the fractional excretion rate of Na(+) and K(+) and absolute excretion of Na(+) and K(+) were significantly blunted in Romk(-/-) mice, consistent with a major salt transport defect in the TAL. In contrast, hydrochlorothiazide produced an exaggerated natriuresis in Romk(-/-) mice, indicating upregulation of salt absorption by the DCT. Benzamil resulted in a similar increment in absolute Na excretion in both Romk(-/-) and Romk(+/+), indicating no significant upregulation of Na(+) transport by ENaC in ROMK null mice. Moreover, hydrochlorothiazide increased the fractional K(+) excretion rate in Romk(-/-) mice, confirming our recent observation that maxi-K channels contribute to distal K(+) secretion in the absence of ROMK.
Cantone
Alessandra
A
Dept. of Cellular and Molecular Physiology, Yale School of Medicine, 333 Cedar St., New Haven, CT 06520-8026, USA.
Yang
Xinbo
X
Yan
Qingshang
Q
Giebisch
Gerhard
G
Hebert
Steven C
SC
Wang
Tong
T
D000222:Adaptation, Physiological / Q000502:physiology; D000584:Amiloride / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D001477:Bartter Syndrome / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D027682:Cation Transport Proteins / Q000378:metabolism; D002712:Chlorides / Q000378:metabolism*; D004195:Disease Models, Animal; D004232:Diuretics / Q000494:pharmacology*; D053503:Epithelial Sodium Channels / Q000378:metabolism; D005260:Female; D005665:Furosemide / Q000494:pharmacology; D005919:Glomerular Filtration Rate / Q000187:drug effects / Q000502:physiology; D006852:Hydrochlorothiazide / Q000494:pharmacology*; D008138:Loop of Henle / Q000378:metabolism; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D024661:Potassium Channels, Inwardly Rectifying / Q000235:genetics* / Q000378:metabolism; D011247:Pregnancy; D012964:Sodium / Q000378:metabolism*; D028021:Sodium-Potassium-Chloride Symporters / Q000378:metabolism; D064466:Solute Carrier Family 12, Member 1; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology; D000099236:Solute Carrier Family 11, Member 2
D000584:Amiloride; D027682:Cation Transport Proteins; D002712:Chlorides; D004232:Diuretics; D053503:Epithelial Sodium Channels; D005665:Furosemide; D006852:Hydrochlorothiazide; D024661:Potassium Channels, Inwardly Rectifying; D012964:Sodium; D028021:Sodium-Potassium-Chloride Symporters; D064466:Solute Carrier Family 12, Member 1; D000099236:Solute Carrier Family 11, Member 2; C510693:Kcnj1 protein, mouse; C578715:Slc12a1 protein, mouse; C013407:benzamil