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This Article Full Text Full Text (PDF) All Versions of this Article: 294/6/F1373    most recent 00613.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Google Scholar Articles by Wagner, C. A. Articles by Loffing, J. PubMed PubMed Citation Articles by Wagner, C. A. Articles by Loffing, J.

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

¹Institute of Physiology, Center of Integrative Human Physiology, and ²Institute of Anatomy, University of Zurich, Zurich; ³Department of Medicine, Unit of Anatomy, University of Fribourg, Fribourg, Switzerland; and Departments of ⁴Cellular and Molecular Physiology and ⁵Surgery, Yale Medical School, New Haven, Connecticut

Submitted 25 December 2007 ; accepted in final form 28 February 2008

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 PGE₂ 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 -,β-, and -subunits of the epithelial Na⁺ channel (ENaC) was slightly increased, although only differences for -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.

thick ascending limb of Henle's loop; distal convoluted tubule; thiazide-sensitive NaCl cotransporter; renal outer medulla K⁺ channel; hyperprostaglandin E syndrome

This article has been cited by other articles:

				A. Cantone, X. Yang, Q. Yan, G. Giebisch, S. C. Hebert, and T. Wang Mouse model of type II Bartter's syndrome. I. Upregulation of thiazide-sensitive Na-Cl cotransport activity Am J Physiol Renal Physiol, June 1, 2008; 294(6): F1366 - F1372. [Abstract] [Full Text] [PDF]