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[with no lysine (k)] kinase is a serine/threonine kinase subfamily. Mutations in two of the WNK kinases result in pseudohypoaldosteronism type II (PHA II) characterized by hypertension, hyperkalemia, and metabolic acidosis. Recent studies showed that both WNK1 and WNK4 inhibit ROMK activity. However, little is known about the effect of WNK kinases on Maxi K, a large-conductance Ca 2ϩ and voltage-activated potassium (K) channel. Here, we report that WNK4 wild-type (WT) significantly inhibits Maxi K channel activity in HEK ␣BK stable cell lines compared with the control group. However, a WNK4 dead-kinase mutant, D321A, has no inhibitory effect on Maxi K activity. We further found that WNK4 inhibits total and cell surface protein expression of Maxi K equally compared with control groups. A dominant-negative dynamin mutant, K44A, did not alter the WNK4-mediated inhibitory effect on Maxi K surface expression. Treatment with bafilomycin A1 (a proton pump inhibitor) and leupeptin (a lysosomal inhibitor) reversed WNK4 WT-mediated inhibition of Maxi K total protein expression. These findings suggest that WNK4 WT inhibits Maxi K activity by reducing Maxi K protein at the membrane, but that the inhibition is not due to an increase in clathrin-mediated endocytosis of Maxi K, but likely due to enhancing its lysosomal degradation. Also, WNK4's inhibitory effect on Maxi K activity is dependent on its kinase activity. protein expression; lysosomal degradation WNK [WITH NO LYSINE (K)] KINASE belongs to a subfamily of serine/threonine kinases (55). Mutations in two members of this family, WNK1 and WNK4, result in pseudohypoaldosteronism type II (PHA II). PHA II, also referred to as Gordon's syndrome, is an autosomal dominant disorder, characterized by hypertension, hyperkalemia, and metabolic acidosis (51). This clinical phenotype suggests that WNK kinases might regulate renal potassium (K) channels, such as renal outer medullary potassium channel (ROMK) or Maxi K channels (BK channels) that are responsible for K handling by the distal nephron. A number of studies indicate that WNK kinases constitute a novel signaling pathway that is involved in the regulation of different ion transporters and channels controlling sodium and K homeostasis (23). In kidney tissue, there are two types of apical K channels identified in the distal nephron by patchclamp analysis (38). One type of K channel is a low-conductance secretory K (SK) channel that has high open probability at resting membrane potential and mediates K ϩ secretion under basal conditions. The properties of the SK channel are consistent with those of ROMK. The other type of K channel has a high single-channel conductance (Ͼ100 pS) and channel kinetics similar to Maxi K channels (34). Although it is generally accepted that ROMK is the K ϩ secretory channel in the mammalian distal nephron, recent in vitro and in vivo studies have provided evidence that Maxi K can also serves as a K ϩ secretory channel in renal tubules (37) and that it plays an important role in K ϩ secretion in ROM...

WNK [with no lysine (K)] kinase is a subfamily of serine/threonine kinases. Mutations in two members of this family (WNK1 and WNK4) cause pseudohypoaldosteronism type II featuring hypertension, hyperkalemia, and metabolic acidosis. WNK1 and WNK4 were shown to regulate sodium chloride cotransporter (NCC) activity through phosphorylating SPAK and OSR1. Previous studies including ours have also shown that WNK4 inhibits NCC function and its protein expression. A recent study reported that a phorbol ester inhibits NCC function via activation of extracellular signal-regulated kinase (ERK) 1/2 kinase. In the current study, we investigated whether WNK4 affects NCC via the MAPK ERK1/2 signaling pathway. We found that WNK4 increased ERK1/2 phosphorylation in a dose-dependent manner in mouse distal convoluted tubule (mDCT) cells, whereas WNK4 mutants with the PHA II mutations (E562K and R1185C) lost the ability to increase the ERK1/2 phosphorylation. Hypertonicity significantly increased ERK1/2 phosphorylation in mDCT cells. Knock-down of WNK4 expression by siRNA resulted in a decrease of ERK1/2 phosphorylation. We further showed that WNK4 knock-down significantly increases the cell surface and total NCC protein expressions and ERK1/2 knock-down also significantly increases cell surface and total NCC expression. These data suggest that WNK4 inhibits NCC through activating the MAPK ERK1/2 signaling pathway.

Objective: To systematically assess the effectiveness of core-based exercise for correcting a spinal deformity and improving quality of life in people with scoliosis. Data sources: The PubMed, Embase, Cochrane Library, Cumulative Index of Nursing and Allied Health Literature (CINAHL), and Web of Science databases were searched from inception up to September 30, 2020. Methods: Clinical controlled trials were eligible if they compared the effectiveness of core-based exercise to other nonsurgical interventions in people with scoliosis. The revised Cochrane risk of bias assessment tool for randomized trials and the methodological index for non-randomized studies scale were used to assess the risk of bias. The outcomes included the Cobb angle, the angle of trunk rotation and quality of life. RevMan 5.3 was used, and intergroup differences were determined by calculating mean differences (MD) and 95% confidence intervals (CIs). Results: After screening 1348 studies, nine studies with 325 participants met the inclusion criteria. The exercise group had significantly lower Cobb angles (MD = −2.08, 95% CI: −3.89 to −0.28, P = 0.02) and significantly better quality of life as measured by the Scoliosis Research Society-22 questionnaire (MD = 0.25, 95% CI: 0.02 to 0.49, P = 0.03) than the control groups. However, no significant difference was observed regarding the angle of trunk rotation between groups (MD = −0.69, 95% CI: −2.61 to 1.22, P = 0.48). Furthermore, no serious adverse events were reported. The overall quality of evidence ranged from low to very low. Conclusion: Core-based exercise may have a beneficial role in reducing the Cobb angle and improving quality of life in people with scoliosis in the short term. PROSPERO registration number: CRD42020160509 (Available at http://www.crd.york.ac.uk/prospero/ )

The aim of the study is to determine whether serum 25-hydroxyvitamin D (25(OH)D) deficiency in infants increased odds of urinary tract infection (UTI). A total of 238 infants including 132 patients experiencing a first episode of UTI and 106 controls, aged from 1 to 12 months, were enrolled. Serum 25(OH)D levels were tested through blood sampling. The serum 25(OH)D levels were significantly lower in cases with UTI than controls. The mean serum 25(OH)D levels were 29.09 ± 9.56 ng/mL in UTIs and 38.59 ± 12.41 ng/mL in controls (P < 0.001). Infants with acute pyelonephritis (APN) had lower serum 25(OH)D than those with lower UTI. The multivariate logistic regression analyses showed that serum 25(OH)D < 20 ng/mL (OR 5.619, 95% CI 1.469–21.484, P = 0.012) was positively related to an increased odds of UTI. Vitamin D supplementation (OR 0.298, 95% CI 0.150–0.591; P = 0.001) was associated with a decreased likelihood of UTI. Vitamin D deficiency in infants was associated with an increased odds of UTI. Interventional studies evaluating the role of vitamin D supplementation to reduce the burden of UTI are warranted.

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