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Mouse model of type II Bartter's syndrome. I. Upregulation of thiazide-sensitive Na-Cl cotransport activity

Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, Connecticut

Submitted 26 December 2007 ; accepted in final form 27 March 2008

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.

ROMK knockout; furosemide; hydrochlorothiazide; benzamil

This article has been cited by other articles:

				C. A. Wagner, D. Loffing-Cueni, Q. Yan, N. Schulz, P. Fakitsas, M. Carrel, T. Wang, F. Verrey, J. P. Geibel, G. Giebisch, et al. Mouse model of type II Bartter's syndrome. II. Altered expression of renal sodium- and water-transporting proteins Am J Physiol Renal Physiol, June 1, 2008; 294(6): F1373 - F1380. [Abstract] [Full Text] [PDF]