WNK1 and WNK4 mutations have been reported to cause pseudohypoaldosteronism type II (PHAII), an autosomal-dominant disorder characterized by hyperkalemia and hypertension. To elucidate the molecular pathophysiology of PHAII, we generated Wnk4(D561A/+) knockin mice presenting the phenotypes of PHAII. The knockin mice showed increased apical expression of phosphorylated Na-Cl cotransporter (NCC) in the distal convoluted tubules. Increased phosphorylation of the kinases OSR1 and SPAK was also observed in the knockin mice. Apical localization of the ROMK potassium channel and transepithelial Cl(-) permeability in the cortical collecting ducts were not affected in the knockin mice, whereas activity of epithelial Na(+) channels (ENaC) was increased. This increase, however, was not evident after hydrochlorothiazide treatment, suggesting that the regulation of ENaC was not a genetic but a secondary effect. Thus, the pathogenesis of PHAII caused by a missense mutation of WNK4 was identified to be increased function of NCC through activation of the OSR1/SPAK-NCC phosphorylation cascade.
CLC-K1 is a kidney-specific chloride channel that mediates transepithelial chloride transport in the thin ascending limb of Henle's loop (tAL) in the inner medulla. Transport of NaCl in the tAL is thought to be a component of urinary concentration in a passive model of the countercurrent multiplication system, but there has been no direct evidence that CLC-K1 is involved in urine concentration. To analyse the physiological function of CLC-K1 in vivo, we generated mice lacking CLC-K1 by targeted gene disruption. Clcnk1-/- mice were physically normal appearance, but produced approximately five times more urine than Clcnk1+/- and Clcnk1+/+ mice. After 24 hours of water deprivation, Clcnk1-/- mice were severely dehydrated and lethargic, with a decrease of approximately 27% in body weight. Intraperitoneal injection of the V2 agonist 1-deamino-8-D-arginine vasopressin (dDAVP) induced a threefold increase in urine osmolarity in Clcnk1+/- and Clcnk1+/+ mice, whereas only a minimal increase was seen in Clcnk1-/- mice, indicating nephrogenic diabetes insipidus. After in vitro perfusion of the tAL, the lumen-to-bath chloride gradient did not produce a diffusion potential in Clcnk1-/- mice in contrast to Clcnk1+/+ and Clcnk1+/- mice. These results establish that CLC-K1 has a role in urine concentration, and that the countercurrent system in the inner medulla is involved in the generation and maintenance of hypertonic medullary interstitium.
Multilineage-differentiating stress-enduring (Muse) cells are nontumorigenic endogenous pluripotent-like stem cells that can be collected from various organs. Intravenously administered Muse cells have been shown to spontaneously migrate to damaged tissue and replenish lost cells, but the effect in FSGS is unknown. We systemically administered human bone marrow-derived Muse cells without concurrent administration of immunosuppressants to severe combined immune-deficient (SCID) and BALB/c mouse models with adriamycin-induced FSGS (FSGS-SCID and FSGS-BALB/c, respectively). In FSGS-SCID mice, human Muse cells preferentially integrated into the damaged glomeruli and spontaneously differentiated into cells expressing markers of podocytes (podocin; 31%), mesangial cells (megsin; 13%), and endothelial cells (CD31; 41%) without fusing to the host cells; attenuated glomerular sclerosis and interstitial fibrosis; and induced the recovery of creatinine clearance at 7 weeks. Human Muse cells induced similar effects in FSGS-BALB/c mice at 5 weeks, despite xenotransplant without concurrent immunosuppressant administration, and led to improvement in urine protein, creatinine clearance, and plasma creatinine levels more impressive than that in the FSGS-SCID mice at 5 weeks. However, functional recovery in FSGS-BALB/c mice was impaired at 7 weeks due to immunorejection, suggesting the importance of Muse cell survival as glomerular cells in the FSGS kidney for tissue repair and functional recovery. In conclusion, Muse cells are unique reparative stem cells that preferentially home to damaged glomeruli and spontaneously differentiate into glomerular cells after systemic administration. Introduction of genes to induce differentiation is not required before Muse cell administration; thus, Muse cells may be a feasible therapeutic strategy in FSGS.
We investigated the location, size, and shape of cervical lymph nodes in head and neck cancer, using a 7.5-MHz ultrasound scanner. First, the different criteria for normal size were obtained for cervical lymph nodes in each region; lymph nodes greater than 9 mm in thickness in the internal jugular chain or greater than 7 mm in thickness in the submandibular and submental chains should be suspected of harboring metastatic foci. Second, meta· static nodes showed a more rounded configuration than A precise evaluation of the presence of meta· stasis to the cervical lymph nodes is mandatory in the management of head and neck malignancies. X-ray computed tomography (CT), 1 magnetic resonance imaging (MRI), and ultrasound 2 -4 have been used to evaluate lymphadenopathy in the neck. Recent reports on ultrasonography in the neck suggest its high efficiency in detecting small, nonpalpable lymphadenopathy. Although size has been used to diagnose me~ tastasis in lymph nodes, few studies have dealt with their internal structure.To determine the size and shape criteria for normal lymph nodes in each region in the neck, as well as to clarify any abnormal patterns of internal structure in metastatic lymph nodes, we conducted a correlative Received July 20, 1987, from the Departments of "Radiology, fOral Surgery. *Otolaryngology. and §Laboratory Medicine, School of Medi· cine, Shinshu University. Asahi, Matsumoto, Japan. Revised manuscript accepted for publication October 29, 1987. Address correspondence and reprint requests to Dr. F. Sakai: De· partment of Radiology, School of Medicine, Shinshu University, Asahi, Matsumoto, 390, Japan. nonmetastatic ones. Third, a comparative study of metastatic lymph nodes between the in vivo and in vitro ultrasonograms and the corresponding histopathological findings disclosed that an echogenic region in an ultrasonogram of a metastatic node was caused by coagulation necrosis, and a cystic area of liquefaction necrosis. KEY WORDS; ultrasonography, lymphadenopathy, echogenicity, size of lymph node. (/ Ultrasound Med 7: 305, 1988)
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