Intensified blood-pressure control, with target 24-hour blood-pressure levels in the low range of normal, confers a substantial benefit with respect to renal function among children with chronic kidney disease. Reappearance of proteinuria after initial successful pharmacologic blood-pressure control is common among children who are receiving long-term ACE inhibition. (ClinicalTrials.gov number, NCT00221845.)

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The term Bartter syndrome encompasses a heterogeneous group of autosomal recessive salt-losing nephropathies that are caused by disturbed transepithelial sodium chloride reabsorption in the distal nephron. Mutations have been identified in the NKCC2 (Na(+)-K(+)-2Cl(-)) cotransporter and ROMK potassium channel, which cooperate in the process of apical sodium chloride uptake, and ClC-Kb chloride channels, which mediate basolateral chloride release. Recently, mutations in barttin, a protein not related to any known ion transporter or channel, were described in BSND, a variant of Bartter syndrome associated with sensorineural deafness. Here we show that barttin functions as an activator of ClC-K chloride channels. Expression of barttin together with ClC-K in Xenopus oocytes increased ClC-K current amplitude, changed ClC-K biophysical properties, and enhanced ClC-K abundance in the cell membrane. Co-immunoprecipitation revealed a direct interaction of barttin with ClC-K. We performed in situ hybridization on rat kidney slices and RT-PCR analysis on microdissected nephron segments to prove co-expression of barttin, ClC-K1 and ClC-K2 along the distal nephron. Functional analysis of BSND-associated point mutations revealed impaired ClC-K activation by barttin. The results demonstrate regulation of a CLC chloride channel by an accessory protein and indicate that ClC-K activation by barttin is required for adequate tubular salt reabsorption.

Inward-rectifier K ؉ channels of the ROMK (Kir1.1) subtype are responsible for K ؉ secretion and control of NaCl absorption in the kidney. A hallmark of these channels is their gating by intracellular pH in the neutral range. Here we show that a lysine residue close to TM1, identified previously as a structural element required for pH-induced gating, is protonated at neutral pH and that this protonation drives pH gating in ROMK and other K ir channels. Such anomalous titration of this lysine residue (Lys-80 in K ir1.1) is accomplished by the tertiary structure of the Kir protein: two arginines in the distant N and C termini of the same subunit (Arg-41 and Arg-311 in K ir1.1) are located in close spatial proximity to the lysine allowing for electrostatic interactions that shift its pK a into the neutral pH range. Structural disturbance of this triad as a result from a number of point mutations found in patients with antenatal Bartter syndrome shifts the pK a of the lysine residue off the neutral pH range and results in channels permanently inactivated under physiological conditions. Thus, the results provide molecular understanding for normal pH gating of K ir channels as well as for the channel defects found in patients with antenatal Bartter syndrome.

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Gitelman syndrome is an inherited renal disorder characterized by impaired NaCl reabsorption in the distal convoluted tubule and secondary hypokalemic alkalosis. In clinical practice, it is distinguished from other hypokalemic tubulopathies by the presence of both hypomagnesemia and normocalcemic hypocalciuria. To date, only mutations in a single gene encoding the thiazide-sensitive NaCl cotransporter have been found as the molecular basis of GS. We describe three unrelated patients presenting with the typical laboratory findings of GS. Mutational analysis in these patients revealed no abnormality in the SLC12A3 gene. Instead, all patients were found to carry previously described mutations in the CLCNKB gene, which encodes the kidney-specific chloride channel ClC-Kb, raising the possibility of genetic heterogeneity. Review of the medical histories revealed manifestation of the disease within the first year of life in all cases. Clinical presentation included episodes of dehydration, weakness, and failure to thrive, much more suggestive of classic Bartter syndrome than of GS. The coexistence of hypomagnesemia and hypocalciuria was not present from the beginning. In the follow-up, however, a drop of both parameters below normal range was a consistent finding reflecting a transition from cBS to GS phenotype. The phenotypic overlap may indicate a physiologic cooperation of the apical thiazide-sensitive NaCl cotransporter and the basolateral chloride channel for salt reabsorption in the distal convoluted tubule. Abbreviations GS, Gitelman syndrome cBS, classic Bartter syndrome DCT, distal convoluted tubule NCCT, thiazide-sensitive NaCl cotransporter ClC-Kb, kidney-specific basolateral chloride channel TAL, thick ascending limb of Henle's loop HPS/aBS, hyperprostaglandin E/antenatal Bartter syndrome GS (MIM 263800) is an inherited renal tubular disorder characterized by impaired conservation of potassium and magnesium (1). The mode of inheritance is autosomal-recessive. The first clinical presentation is usually observed during childhood or adolescence and may include transient episodes of weakness, paresthesia, and tetany. The course of disease is generally mild and some patients even remain asymptomatic (2, 3, 4). GS patients share several biochemical findings with the more severe cBS, such as hypokalemia, metabolic alkalosis, and elevated plasma aldosterone levels (5). However, the coexistence of hypomagnesemia and hypocalciuria is considered a pathognomonic laboratory finding in GS that allows the differentiation from cBS (6).Both the observation that the electrolyte disturbances in GS resemble the effect of chronic thiazide administration (7, 8) and the results of clearance studies have pointed to a defect in the distal thiazide-sensitive sodium chloride transport (9). This hypothesis has been substantiated by the demonstration that GS is caused by mutations in the SLC12A3 gene, which encodes the NCCT of the DCT (10). Meanwhile, more than 100 mutations throughout the NCCT have been described in GS patients, sugge...

The molecular basis of inherited salt-losing tubular disorders with secondary hypokalemia has become much clearer in the past two decades. Two distinct segments along the nephron turned out to be affected, the thick ascending limb of Henle's loop and the distal convoluted tubule, accounting for two major clinical phenotypes, hyperprostaglandin E syndrome and Bartter-Gitelman syndrome. To date, inactivating mutations have been detected in six different genes encoding for proteins involved in renal transepithelial salt transport. Careful examination of genetically defined patients ("human knockouts") allowed us to determine the individual role of a specific protein and its contribution to the overall process of renal salt reabsorption. The recent generation of several genetically engineered mouse models that are deficient in orthologous genes further enabled us to compare the human phenotype with the animal models, revealing some unexpected interspecies differences. As the first line treatment in hyperprostaglandin E syndrome includes cyclooxygenase inhibitors, we propose some hypotheses about the mysterious role of PGE(2) in the etiology of renal salt-losing disorders.

Autosomal nephrogenic diabetes insipidus (NDI), a disease in which the kidney is unable to concentrate urine in response to vasopressin, is caused by mutations in the Aquaporin-2 (AQP2) gene. Analysis of a new family with dominant NDI revealed a single nucleotide deletion (727deltaG) in one AQP2 allele, which encoded an AQP2 mutant with an altered and extended C-terminal tail. When expressed in oocytes, the tetrameric AQP2-727deltaG was retained within the cell. When co-expressed, AQP2-727deltaG, but not a mutant in recessive NDI (AQP2-R187C), formed hetero-oligomers with wild-type (wt) AQP2 and reduced the water permeability of these oocytes, because of a reduced plasma membrane expression of wt-AQP2. Expressed in renal epithelial cells, AQP2-727deltaG predominantly localized to the basolateral membrane and late endosomes/lysosomes, whereas wt-AQP2 was expressed in the apical membrane. Upon co-expressing in these cells, wt-AQP2 and AQP2-727deltaG mainly co-localized to late endosomes/lysosomes. In conclusion, hetero-oligomerization of AQP2-727deltaG with wt-AQP2 and consequent mistargeting of this complex to late endosomes/lysosomes results in absence of AQP2 in the apical membrane, which can explain dominant NDI in this family. Together with other mutants in dominant NDI, our data reveal that a misrouting, instead of a lack of function, is a general mechanism for the 'loss of function' phenotype in dominant NDI and visualizes for the first time a mislocalization of a wild-type protein to late endosomes/lysosomes in polarized cells after oligomerization with a mutant protein.