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These effects are mediated by vasopressin 2 receptors (V<jats:sub>2<\/jats:sub>R) and release of intracellular G<jats:sub>s<\/jats:sub>-mediated cAMP to activate epithelial transport proteins. Inactivating mutations in the V<jats:sub>2<\/jats:sub>R gene lead to the X-linked form of nephrogenic diabetes insipidus (NDI), which has chiefly been related with impaired aquaporin 2-mediated water reabsorption in the collecting ducts. Previous work also suggested the AVP-V<jats:sub>2<\/jats:sub>R-mediated activation of Na<jats:sup>+<\/jats:sup>-K<jats:sup>+<\/jats:sup>-2Cl<jats:sup>\u2212<\/jats:sup>-cotransporters (NKCC2) along the thick ascending limb (TAL) in the context of urine concentration, but its individual contribution to NDI or, more generally, to overall renal function was unclear. We hypothesized that V<jats:sub>2<\/jats:sub>R-mediated effects in TAL essentially determine its reabsorptive function. To test this, we reevaluated V<jats:sub>2<\/jats:sub>R expression. Basolateral membranes of medullary and cortical TAL were clearly stained, whereas cells of the macula densa were unreactive. A dominant-negative, NDI-causing truncated V<jats:sub>2<\/jats:sub>R mutant (Ni3-Glu242stop) was then introduced into the rat genome under control of the Tamm-Horsfall protein promoter to cause a tissue-specific AVP-signaling defect exclusively in TAL. Resulting Ni3-V<jats:sub>2<\/jats:sub>R transgenic rats revealed decreased basolateral but increased intracellular V<jats:sub>2<\/jats:sub>R signal in TAL epithelia, suggesting impaired trafficking of the receptor. Rats displayed significant baseline polyuria, failure to concentrate the urine in response to water deprivation, and hypercalciuria. NKCC2 abundance, phosphorylation, and surface expression were markedly decreased. In summary, these data indicate that suppression of AVP-V<jats:sub>2<\/jats:sub>R signaling in TAL causes major impairment in renal fluid and electrolyte handling. 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