The heteromeric inwardly rectifying Kir4.1/Kir5.1 K + channel underlies the basolateral K + conductance in the distal nephron and is extremely sensitive to inhibition by intracellular pH. The functional importance of Kir4.1/Kir5.1 in renal ion transport has recently been highlighted by mutations in the human Kir4.1 gene ( KCNJ10 ) that result in seizures, sensorineural deafness, ataxia, mental retardation, and electrolyte imbalance (SeSAME)/epilepsy, ataxia, sensorineural deafness, and renal tubulopathy (EAST) syndrome, a complex disorder that includes salt wasting and hypokalemic alkalosis. Here, we investigated the role of the Kir5.1 subunit in mice with a targeted disruption of the Kir5.1 gene ( Kcnj16 ). The Kir5.1 −/− mice displayed hypokalemic, hyperchloremic metabolic acidosis with hypercalciuria. The short-term responses to hydrochlorothiazide, an inhibitor of ion transport in the distal convoluted tubule (DCT), were also exaggerated, indicating excessive renal Na + absorption in this segment. Furthermore, chronic treatment with hydrochlorothiazide normalized urinary excretion of Na + and Ca 2+ , and abolished acidosis in Kir5.1 −/− mice. Finally, in contrast to WT mice, electrophysiological recording of K + channels in the DCT basolateral membrane of Kir5.1 −/− mice revealed that, even though Kir5.1 is absent, there is an increased K + conductance caused by the decreased pH sensitivity of the remaining homomeric Kir4.1 channels. In conclusion, disruption of Kcnj16 induces a severe renal phenotype that, apart from hypokalemia, is the opposite of the phenotype seen in SeSAME/EAST syndrome. These results highlight the important role that Kir5.1 plays as a pH-sensitive regulator of salt transport in the DCT, and the implication of these results for the correct genetic diagnosis of renal tubulopathies is discussed.

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Inherited and acquired disorders that enhance the activity of transporters mediating renal tubular Na + reabsorption are well established causes of hypertension. It is unclear, however, whether primary activation of an Na + -independent chloride transporter in the kidney can also play a pathogenic role in this disease. Here, mice overexpressing the chloride transporter pendrin in intercalated cells of the distal nephron (Tg B1-hPDS mice) displayed increased renal absorption of chloride. Compared with normal mice, these transgenic mice exhibited a delayed increase in urinary NaCl and ultimately, developed hypertension when exposed to a high-salt diet. Administering the same sodium intake as NaHCO 3 instead of NaCl did not significantly alter BP, indicating that the hypertension in the transgenic mice was chloride-sensitive. Moreover, excessive chloride absorption by pendrin drove parallel absorption of sodium through the epithelial sodium channel ENaC and the sodium-driven chloride/bicarbonate exchanger (Ndcbe), despite an appropriate downregulation of these sodium transporters in response to the expanded vascular volume and hypertension. In summary, chloride transport in the distal nephron can play a primary role in driving NaCl transport in this part of the kidney, and a primary abnormality in renal chloride transport can provoke arterial hypertension. Thus, we conclude that the chloride/bicarbonate exchanger pendrin plays a major role in controlling net NaCl absorption, thereby influencing BP under conditions of high salt intake.

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Dermatomyositis is a rare autoimmune disorder in which an abnormal immune reaction against vascular endothelial antigens and endomysium leads to obstructive inflammatory changes of blood vessels within muscles, skin and other tissues. The disease is characterized by involvement of muscles, and less frequently of other systems, including the gastrointestinal tract, heart and lungs. Dermatomyositis may be diagnosed based on a detailed patient history, through clinical examination, detection of characteristic physical findings and certain specialized tests. Additional imaging studies may be performed to aid in the diagnosis. These include magnetic resonance imaging and ultrasound of the affected muscles. Magnetic resonance imaging is the modality of choice in the diagnostic work-up and monitoring of dermatomyositis affecting muscles, fasciae, and the subcutis. It may recognize acute inflammatory edematous changes in the affected muscles as well fatty replacement and atrophy. The role of ultrasound to diagnose and follow up muscle echogenicity, vascularity, elasticity and volume during treatment has increased over the last years in both adults and children. Ultrasound is used to discriminate between high and low disease activity, may show features of subclinical disease and may be used to confirm remission.

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