Phenotype Resembling Gitelman's Syndrome in Mice Lacking the Apical Na+-Cl− Cotransporter of the Distal Convoluted Tubule

Abstract

Mutations in the gene encoding the thiazide-sensitive Na ؉ -Cl ؊ cotransporter (NCC) of the distal convoluted tubule cause Gitelman's syndrome, an inherited hypokalemic alkalosis with hypomagnesemia and hypocalciuria. These metabolic abnormalities are secondary to the deficit in NaCl reabsorption, but the underlying mechanisms are unclear. To gain a better understanding of the role of NCC in sodium and fluid volume homeostasis and in the pathogenesis of Gitelman's syndrome, we used gene targeting to prepare an NCC-deficient mouse. Null mutant (Ncc ؊/؊ ) mice appear healthy and are normal with respect to acid-base balance, plasma electrolyte concentrations, serum aldosterone levels, and blood pressure. Ncc ؊/؊ mice retain Na ؉ as well as wild-type mice when fed a Na ؉ -depleted diet; however, after 2 weeks of Na ؉ depletion the mean arterial blood pressure of Ncc ؊/؊ mice was significantly lower than that of wild-type mice. In addition, Ncc ؊/؊ mice exhibited increased renin mRNA levels in kidney, hypomagnesemia and hypocalciuria, and morphological changes in the distal convoluted tubule. These data indicate that the loss of NCC activity in the mouse causes only subtle perturbations of sodium and fluid volume homeostasis, but renal handling of Mg 2؉ and Ca 2؉ are altered, as observed in Gitelman's syndrome.

The sodium chloride cotransporter SLC12A3: new roles in sodium, potassium, and blood pressure regulation

“…On the other hand, heterozygous mutations in NCC may prevent hypertension and cardiovascular diseases [52] and improve bone-density [17] likely because they induce mild sodium excretion and a positive calcium balance. NCC knockout mice recapitulate the phenotype of Gitelman syndrome, although some features become manifest only when the animals are challenged [73,80,105,139]. In line with the current model of NCC regulation (Figure 3), genetically modified mice with overexpression of WNK4, deficiency in SPAK or its kinase domain, also exhibit features of Gitelman syndrome [61,88,94,139], although such mutations have not been identified in humans.…”

Pendrin Regulation in Mouse Kidney Primarily Is Chloride-Dependent

“…Physiologic data from the NCC Ϫ/Ϫ and NCC ϩ/ϩ mice that were used in these studies are summarized in Table 4. As described previously (19), when fed a Na ϩ -replete diet, NCC Ϫ/Ϫ mice were normal with respect to their weight, plasma electrolyte concentrations, and acid-base balance. and 85-kD molecular forms of the protein (348 Ϯ 34 and 120 Ϯ 5% in NCC Ϫ/Ϫ versus 100 Ϯ 9 and 100 Ϯ 6% in NCC ϩ/ϩ ; P Ͻ 0.0001 and P ϭ 0.03 for the 70-and 85-kD bands, respectively).…”

“…Animals were 5 to 6 mo of age and weighed 28 to 30 g. NaCl Co-Transporter (NCC) Knockout Mice. Mice were generated by a standard gene-targeting technique as described previously (19). Eight adult homozygous NCC-deficient male mice (NCC Ϫ/Ϫ ) and eight littermate wild-type mice (NCC ϩ/ϩ ) were used for this series.…”

The epithelial calcium channels TRPV5 and TRPV6: regulation and implications for disease

“…In addition, in Gitelman's syndrome, a recessive disorder caused by mutations in the gene encoding NCC, hypocalciuria is invariably present (Lemmink et al 1996;Schultheis et al 1998). Some hypotheses concerning the mechanism responsible for this hypocalciuria also center on stimulation of active Ca 2+ transport (Ellison 2000).…”