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      Thiazide-Sensitive Cotransporter mRNA Expression Is Not Altered in Three Models of Hypertension

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          Background/Aims: Several lines of evidence support that the kidney is involved in the increase of arterial blood pressure, and some genetic studies suggest that the thiazide-sensitive Na<sup>+</sup>:Cl<sup>–</sup> cotransporter could be implicated in the development of hypertension. In the present study, we analyzed the Na<sup>+</sup>:Cl<sup>–</sup> cotransporter mRNA levels in the kidney during the development of hypertension in three experimental models. Methods: The first model included 18 spontaneously hypertensive rats studied at 4, 10, and 16 weeks of age. The second model included 28 Wistar rats with two-kidney, one-clip Goldblatt hypertension studied at 7, 14, 21, and 28 days. The third model included 6 Wistar rats treated with N<sup>G</sup>-nitro- L-arginine methyl ester during 10 days. Respective controls were studied for all models. At the end of each experimental period, the systolic blood pressure was measured in the tail by plethysmography. Individual renal cortex total RNA was extracted, and the mRNA levels of the thiazide-sensitive Na<sup>+</sup>:Cl<sup>–</sup> cotransporter were assessed following a semiquantitative RT-PCR strategy. Results: All experimental models developed systemic hypertension. However, the level of mRNA expression of the Na<sup>+</sup>:Cl<sup>–</sup> cotransporter did not change in any of the models studied as compared with their respective controls. Conclusion: Our results suggest that a change in mRNA levels of the thiazide-sensitive Na<sup>+</sup>:Cl<sup>–</sup> cotransporter is not associated with the development of hypertension in spontaneously hypertensive rats, in rats with renovascular hypertension, nor in rats with hypertension induced by nitric oxide synthesis inhibition.

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          Bartter's syndrome, hypokalaemic alkalosis with hypercalciuria, is caused by mutations in the Na-K-2Cl cotransporter NKCC2.

          Inherited hypokalaemic alkalosis with low blood pressure can be divided into two groups-Gitelman's syndrome, featuring hypocalciuria, hypomagnesaemia and milder clinical manifestations, and Bartter's syndrome, featuring hypercalciuria and early presentation with severe volume depletion. Mutations in the renal Na-Cl cotransporter have been shown to cause Gitelman's syndrome. We demonstrate linkage of Bartter's syndrome to the renal Na-K-2Cl cotransporter gene NKCC2, and identify frameshift or non-conservative missense mutations for this gene that co-segregate with the disease. These findings demonstrate the molecular basis of Bartter's syndrome, provide the basis for molecular classification of patients with inherited hypokalaemic alkalosis, and suggest potential phenotypes in heterozygous carriers of NKCC2 mutations.
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            Genetic heterogeneity of Bartter's syndrome revealed by mutations in the K+ channel, ROMK.

            Mutations in the Na-K-2Cl cotransporter (NKCC2), a mediator of renal salt reabsorption, cause Bartter's syndrome, featuring salt wasting, hypokalaemic alkalosis, hypercalciuria and low blood pressure. NKCC2 mutations can be excluded in some Bartter's kindreds, prompting examination of regulators of cotransporter activity. One regulator is believed to be ROMK, an ATP-sensitive K+ channel that 'recycles' reabsorbed K+ back to the tubule lumen. Examination of the ROMK gene reveals mutations that co-segregate with the disease and disrupt ROMK function in four Bartter's kindreds. Our findings establish the genetic heterogeneity of Bartter's syndrome, and demonstrate the physiologic role of ROMK in vivo.
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              Mutations in subunits of the epithelial sodium channel cause salt wasting with hyperkalaemic acidosis, pseudohypoaldosteronism type 1.

              Autosomal recessive pseudohypoaldosteronism type I is a rare life-threatening disease characterized by severe neonatal salt wasting, hyperkalaemia, metabolic acidosis, and unresponsiveness to mineralocorticoid hormones. Investigation of affected offspring of consanguineous union reveals mutations in either the alpha or beta subunits of the amiloride-sensitive epithelial sodium channel in five kindreds. These mutations are homozygous in affected subjects, co-segregate with the disease, and introduce frameshift, premature termination or missense mutations that result in loss of channel activity. These findings demonstrate the molecular basis and explain the pathophysiology of this disease.

                Author and article information

                Kidney Blood Press Res
                Kidney and Blood Pressure Research
                S. Karger AG
                24 January 2001
                : 24
                : 1
                : 57-63
                aMolecular Physiology Unit, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán and Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, bDepartment of Nephrology, Instituto Nacional de Cardiología Ignacio Chávez, and cDepartment of Pharmacology and Toxicology, Cinvestav, IPN, Mexico City, Mexico
                54207 Kidney Blood Press Res 2001;24:57–63
                © 2001 S. Karger AG, Basel

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                Page count
                Figures: 5, References: 30, Pages: 7
                Self URI (application/pdf): https://www.karger.com/Article/Pdf/54207
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