RESUMEN
By analysing the pathogenesis of a hereditary hypertensive disease, PHAII (pseudohypoaldosteronism type II), we previously discovered that WNK (with-no-lysine kinase)-OSR1/SPAK (oxidative stress-responsive 1/Ste20-like proline/alanine-rich kinase) cascade regulates NCC (Na-Cl co-transporter) in the DCT (distal convoluted tubules) of the kidney. However, the role of WNK4 in the regulation of NCC remains controversial. To address this, we generated and analysed WNK4-/- mice. Although a moderate decrease in SPAK phosphorylation and a marked increase in WNK1 expression were evident in the kidneys of WNK4-/- mice, the amount of phosphorylated and total NCC decreased to almost undetectable levels, indicating that WNK4 is the major WNK positively regulating NCC, and that WNK1 cannot compensate for WNK4 deficiency in the DCT. Insulin- and low-potassium diet-induced NCC phosphorylation were abolished in WNK4-/- mice, establishing that both signals to NCC were mediated by WNK4. As shown previously, a high-salt diet decreases phosphorylated and total NCC in WNK4+/+ mice via AngII (angiotensin II) and aldosterone suppression. This was not ameliorated by WNK4 knock out, excluding the negative regulation of WNK4 on NCC postulated to be active in the absence of AngII stimulation. Thus, WNK4 is the major positive regulator of NCC in the kidneys.
Asunto(s)
Túbulos Renales Distales/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Angiotensina II/genética , Angiotensina II/metabolismo , Animales , Transporte Iónico/fisiología , Túbulos Renales Distales/citología , Ratones , Ratones Noqueados , Fosforilación/fisiología , Proteínas Serina-Treonina Quinasas/genética , Transducción de Señal/fisiología , Miembro 3 de la Familia de Transportadores de Soluto 12/genética , Miembro 3 de la Familia de Transportadores de Soluto 12/metabolismoRESUMEN
A 60-year-old female who had been ill with ulcerative colitis for more than ten years presented with upper abdominal pain. A flare-up of ulcerative colitis was unlikely, because she did not report rectal bleeding, altered bowel habit, and changes of stool form. A poorly defined mass with mild tenderness was palpable in the upper abdomen, with increased levels of serum pancreatic enzymes, leading us to suspect pancreatic disease. Although CT scan revealed no abnormalities in the pancreas, a well-defined, heterogeneous soft tissue mass was found in the small bowel mesentery. Although several different diagnoses were considered, characteristic features on CT strongly supported diagnosis of sclerosing mesenteritis. The symptoms resolved quickly without specific treatment. The mesenteric lesion has never changed and no unfavorable events have yet occurred.