Pharmacotyping of hypokalaemic salt‐losing tubular disorders

Reinalter, Stephan C.; Jeck, Nikola; Peters, Melanie; Seyberth, Hannsjörg W.

doi:10.1111/j.1365-201x.2004.01325.x

Cited by 39 publications

(33 citation statements)

References 41 publications

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“…The causative mutations are located in the CLCNKB gene encoding the basolateral chloride channel (ClC-Kb) (6,7), which is located in the thick ascending limb of Henle's loop (TAL) and the distal tubule (DCT) (7). The characteristics of cBS are similar to those observed during combined thiazide and furosemide treatments (8).…”

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Simultaneous Mutations in the CLCNKB and SLC12A3 Genes in Two Siblings with Phenotypic Heterogeneity in Classic Bartter Syndrome

Bettinelli¹,

Borsa

Syrén

et al. 2005

Pediatr Res

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Two siblings (brother and sister) with renal tubular hypokalemic alkalosis underwent clinical, biochemical and molecular investigations. Although the biochemical findings were similar (including hypokalemia, metabolic alkalosis, hyperreninemia, hyperaldosteronism and normal blood pressure), the clinical findings were different: the boy, who also presented syndromic signs, developed glomerular proteinuria and renal biopsy revealed focal segmental glomerular sclerosis; the girl showed the typical signs of classic Bartter syndrome. As described in a previous paper, a heterozygous mutation (frameshift 2534delT) was demonstrated in the gene encoding the thiazide-sensitive NaCl co-transporter (SLC12A3) of the distal convoluted tubule; the second molecular analysis revealed a compound heterozygous mutation (A61D/V149E) in the CLCNKB chloride channel gene in both subjects, inherited in trans from the parents. The children were finally diagnosed as having classic Bartter syndrome. These cases represent the first report of the simultaneous presence of heterozygous and compound heterozygous mutations in the SLC12A3 and CLCNKB genes, both of which are involved in renal salt losing tubulopathies, and confirm previous observations regarding classic Bartter syndrome phenotype variability in the same kindred. Bartter syndromes are inherited disorders characterized by hypokalemia, metabolic alkalosis, hyperreninemic-hyperaldosteronism and renal salt wasting in the presence of normal blood pressure that have at least three different phenotypes: a) antenatal Bartter syndrome (aBS) [OMIM 241200 and 601678] that is characterized by polyhydramnios, premature delivery, a failure to thrive, hypercalciuria and nephrocalcinosis (1), and may be caused by genetic variants in the genes encoding the luminal Na-K-2Cl co-transporter (2) and the ROMK potassium channel (3); b) the Bartter syndrome associated with sensorineural deafness [OMIM 602522] (4), in which the defects reside in the BSND gene (5); and c) classic Bartter syndrome (cBS) [OMIM 607364] which usually onsets in the first year of life.The main findings in cBS are a failure to thrive and marked salt wasting, and there may be nephrocalcinosis and hypercalciuria (6). The causative mutations are located in the CLCNKB gene encoding the basolateral chloride channel (ClC-Kb) (6,7), which is located in the thick ascending limb of Henle's loop (TAL) and the distal tubule (DCT) (7). The characteristics of cBS are similar to those observed during combined thiazide and furosemide treatments (8).Gitelman syndrome (GS) [OMIM 263800] is a different form of inherited hypokalemic metabolic alkalosis that usually onsets during childhood but may also emerge in adult life (9). It is characterized by hypomagnesemia and hypocalciuria, muscle weakness and tetanic crises, and its phenotype is due to mutations in the gene encoding the thiazide-sensitive NaCl co-transporter (SLC12A3) expressed in the DCT (10,11). Unlike cBS, GS resembles the effect of long-term thiazide administration alone (8).The over...

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confidence: 50%

“…It is characterized by hypomagnesemia and hypocalciuria, muscle weakness and tetanic crises, and its phenotype is due to mutations in the gene encoding the thiazide-sensitive NaCl co-transporter (SLC12A3) expressed in the DCT (10,11). Unlike cBS, GS resembles the effect of long-term thiazide administration alone (8).…”

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confidence: 99%

Simultaneous Mutations in the CLCNKB and SLC12A3 Genes in Two Siblings with Phenotypic Heterogeneity in Classic Bartter Syndrome

Bettinelli¹,

Borsa

Syrén

et al. 2005

Pediatr Res

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“…The differential sensitivities to diuretics has established that the defect in HPS was localized to the TAL (25). Thus individuals with HPS exhibit impaired diuretic and natriuretic responses to furosemide, while the effect of this diuretic in Gitelman's disorder is normal (22). In contrast, individuals with Gitelman's disorder exhibit a markedly reduced response to thiazide diuretics that inhibit the thiazide-sensitive NaCl cotransporter localized in the distal convoluted tubule (DCT), while the response to this diuretic is exaggerated in HPS.…”

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confidence: 97%

“…HPS is a severe form of Bartter's syndrome, a hypokalemic renal saltwasting disorder characterized by metabolic alkalosis, normotensive hyperaldosteronism, and increased renin and PGE 2 production (7,22). Despite the absence of ROMK, renal K ϩ wasting and hypokalemia are observed in type II Bartter's, although they are less severe than found in other HPS genotypes [e.g., with mutations in Na ϩ -K ϩ -2Cl Ϫ cotransporter (NKCC)] (20).…”

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“…Consequently, the selected adaptive changes in the Romk Ϫ/Ϫ mouse could have altered the mouse phenotype compared with that observed in HPS. Diuretic pharmacotyping has been used to separate the various phenotypes of hypokalemic renal saltwasting disorders (22) and can be used to compare responses in Romk Ϫ/Ϫ mice and type II HPS. The differential sensitivities to diuretics has established that the defect in HPS was localized to the TAL (25).…”

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

Cantone¹,

Yang²,

Yan³

et al. 2008

American Journal of Physiology-Renal Physiology

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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.

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Ion Channels in Drug Discovery and Safety Pharmacology

Imbrici

Nicolotti

Leonetti

et al. 2018

Methods in Molecular Biology

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Ion channels are membrane proteins involved in almost all physiological processes, including neurotransmission, muscle contraction, pace-making activity, secretion, electrolyte and water balance, immune response, and cell proliferation. Due to their broad distribution in human body and physiological roles, ion channels are attractive targets for drug discovery and safety pharmacology. Over the years ion channels have been associated to many genetic diseases ("channelopathies"). For most of these diseases the therapy is mainly empirical and symptomatic, often limited by lack of efficacy and tolerability for a number of patients. The search for the development of new and more specific therapeutic approaches is therefore strongly pursued. At the same time acquired channelopathies or dangerous side effects (such as proarrhythmic risk) can develop as a consequence of drugs unexpectedly targeting ion channels. Several noncardiovascular drugs are known to block cardiac ion channels, leading to potentially fatal delayed ventricular repolarization. Thus, the search of reliable preclinical cardiac safety testing in early stage of drug discovery is mandatory. To fulfill these needs, both ion channels drug discovery and toxicology strategies are evolving toward comprehensive research approaches integrating ad hoc designed in silico predictions and experimental studies for a more reliable and quick translation of results to the clinic side.Here we discuss two examples of how the combination of in silico methods and patch clamp experiments can help addressing drug discovery and safety issues regarding ion channels.

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Pharmacotyping of hypokalaemic salt‐losing tubular disorders

Cited by 39 publications

References 41 publications

Simultaneous Mutations in the CLCNKB and SLC12A3 Genes in Two Siblings with Phenotypic Heterogeneity in Classic Bartter Syndrome

Simultaneous Mutations in the CLCNKB and SLC12A3 Genes in Two Siblings with Phenotypic Heterogeneity in Classic Bartter Syndrome

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

Ion Channels in Drug Discovery and Safety Pharmacology

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