Mutation of the Na⁺-K⁺-2Cl⁻cotransporter NKCC2 in mice is associated with severe polyuria and a urea-selective concentrating defect without hyperreninemia

Abstract

The bumetanide-sensitive Na(+)-K(+)-2Cl(-) cotransporter NKCC2, located in the thick ascending limb of Henle's loop, plays a critical role in the kidney's ability to concentrate urine. In humans, loss-of-function mutations of the solute carrier family 12 member 1 gene (SLC12A1), coding for NKCC2, cause type I Bartter syndrome, which is characterized by prenatal onset of a severe polyuria, salt-wasting tubulopathy, and hyperreninemia. In this study, we describe a novel chemically induced, recessive mutant mouse line termed Slc12a1(I299F) exhibiting late-onset manifestation of type I Bartter syndrome. Homozygous mutant mice are viable and exhibit severe polyuria, metabolic alkalosis, marked increase in plasma urea but close to normal creatininemia, hypermagnesemia, hyperprostaglandinuria, hypotension,, and osteopenia. Fractional excretion of urea is markedly decreased. In addition, calcium and magnesium excretions are more than doubled compared with wild-type mice, while uric acid excretion is twofold lower. In contrast to hyperreninemia present in human disease, plasma renin concentration in homozygotes is not increased. The polyuria observed in homozygotes may be due to the combination of two additive factors, a decrease in activity of mutant NKCC2 and an increase in medullary blood flow, due to prostaglandin-induced vasodilation, that impairs countercurrent exchange of urea in the medulla. In conclusion, this novel viable mouse line with a missense Slc12a1 mutation exhibits most of the features of type I Bartter syndrome and may represent a new model for the study of this human disease.

Kidney-specific WNK1 inhibits sodium reabsorption in the cortical thick ascending limb

“…Water restriction increases NKCC2 abundance in TAL and vasopressin stimulates trafficking and insertion of NKCC2 to the apical membrane (5, 7). Bartter's mutations in NKCC2 and pharmacological inhibition of NKCC2 impair the urinary concentration mechanism (12,13). The role of cTAL in the urinary concentration is less clear.…”

Common variants of the UMOD promoter associated with blood pressure in a community-based Chinese cohort

“…A mechanism was proposed in which an increase in NKCC2 activity could lead to the expansion of the extracellular volume and thus be associated with HTN. 22 UMOD is synthesized by the tubular cells of the TAL and the early distal convoluted tubule of the kidney. 23 It has been considered that UMOD might influence the colloidal osmotic pressure through the TAL, and thus regulate their active transport along this segment.…”

No Amelioration of Uromodulin Maturation and Trafficking Defect by Sodium 4-Phenylbutyrate in Vivo

“…Daily excretion of solutes was measured. Calculations of creatinine clearance and of fractional excretion of a solute x (FEx) was performed as described previously (17,23).…”