modulates thiazide-sensitive sodium chloride cotransporter abundance via DUSP6-mediated ERK1/2 signaling pathway. Am J Physiol Renal Physiol 308: F1119 -F1127, 2015. First published March 11, 2015 doi:10.1152/ajprenal.00543.2014.-Thiazide-sensitive sodium chloride cotransporter (NCC) plays an important role in maintaining blood pressure. Aldosterone is known to modulate NCC abundance. Previous studies reported that dietary salts modulated NCC abundance through either WNK4 [with no lysine (k) kinase 4]-SPAK (Ste20-related proline alanine-rich kinase) or WNK4-extracellular signalregulated kinase-1 and -2 (ERK1/2) signaling pathways. To exclude the influence of SPAK signaling pathway on the role of the aldosterone-mediated ERK1/2 pathway in NCC regulation, we investigated the effects of dietary salt changes and aldosterone on NCC abundance in SPAK knockout (KO) mice. We found that in SPAK KO mice low-salt diet significantly increased total NCC abundance while reducing ERK1/2 phosphorylation, whereas high-salt diet decreased total NCC while increasing ERK1/2 phosphorylation. Importantly, exogenous aldosterone administration increased total NCC abundance in SPAK KO mice while increasing DUSP6 expression, an ERK1/2-specific phosphatase, and led to decreasing ERK1/2 phosphorylation without changing the ratio of phospho-T53-NCC/total NCC. In mouse distal convoluted tubule (mDCT) cells, aldosterone increased DUSP6 expression while reducing ERK1/2 phosphorylation. DUSP6 Knockdown increased ERK1/2 phosphorylation while reducing total NCC expression. Inhibition of DUSP6 by (E)-2-benzylidene-3-(cyclohexylamino)-2,3-dihydro-1H-inden-1-one increased ERK1/2 phosphorylation and reversed the aldosterone-mediated increments of NCC partly by increasing NCC ubiquitination. Therefore, these data suggest that aldosterone modulates NCC abundance via altering NCC ubiquitination through a DUSP6-dependent ERK1/2 signal pathway in SPAK KO mice and part of the effects of dietary salt changes may be mediated by aldosterone in the DCTs. aldosterone; dietary salt; sodium chloride cotransporter; dual-specificity protein phosphatase 6; ERK1/2; SPAK KO mice THE THIAZIDE-SENSITIVE SODIUM chloride cotransporter (NCC), located in the apical membrane of the distal convoluted tubule (DCT) of the kidney, is responsible for 5-7% of sodium reabsorption (6). NCC plays a key role in the regulation of blood pressure and electrolytes homeostasis (6, 12). Loss-offunction mutations in NCC have been reported to cause Gitelman's syndrome (GS), which is characterized by salt-wasting and low blood pressure (15). NCC is known to be modulated by two different types of regulation, type 1-altering its membrane expression, and type 2-altering the transporter kinetics (17).Aldosterone has been shown to increase the thiazide-sensitive NCC protein in rats (20). Previous studies reported that the regulation of NCC by aldosterone is mediated through a WNK4 [with no lysine (k) kinase 4]-SPAK (Ste20-related proline alanine-rich kinase)-dependent pathway in response to the di...

Purpose Post-acute care is fast developing in China, yet a payment system for post-acute care has not been established. As stroke is the leading cause of mortality and disability in China, patients constitute a large share of post-acute-care patients among all hospitalized patients. This study was to identify the cost determinants and establish a case-mix classification of the post-acute care system for stroke patients in China. Patients and Methods A total of 5401 post-acute stroke patients in seven hospitals of Jinhua City from January 2018 to December 2020 were selected. Demographic characteristics, medical status, functional measures (eg, the Barthel Index, Mini-Mental State Examination, Gugging Swallowing Screen, Hamilton Depression Scale), and cost data were extracted. Generalized linear model (GLM) and quantile regression (QR) were conducted to determine the predictors of cost, and a case-mix classification model was established using the decision-tree analysis. Results The GLM regression revealed that gender, tracheostomy, complication or comorbidity (CC), activities of daily living (ADL), and cognitive impairment were the main variables significantly affecting the hospitalization expenses of post-acute stroke patients. The QR model showed that the gender, tracheostomy and CC factors had a more significant impact on per diem costs on the upper quantiles. In contrast, cognitive impairment had a more substantial effect on the lower quantiles, and ADL significantly impacted the central quantile. Using tracheostomy, CC, and ADL as node variables of the regression tree, 12 classes were generated. The case-mix classification performed reliably and robustly, as measured by the reduction in the variation statistic (RIV=0.46) and class-specific coefficients of variation (CV less than 1.0; range: 0.18–0.81). Conclusion QR has strengths in comprehensively identifying cost predictors across cost groups. Tracheostomy, CC, and ADL significantly can predict the expenses of post-acute care for stroke patients. The established case-mix classification system can inform the future payment policy of post-acute care in China.