Uromodulin Regulates Murine Aquaporin-2 Activity via Thick Ascending Limb-Collecting Duct Cross-Talk during Water Deprivation.

Uromodulin, a urinary protein synthesized and secreted from the thick ascending limb (TAL) of the loop of Henle, is associated with hypertension through the activation of sodium reabsorption in the TAL. Uromodulin is a potential target for hypertension treatment via natriuresis. However, its biological function in epithelial cells of the distal nephron segment, particularly the collecting duct, remains unknown. Herein, we examined the regulation of uromodulin production during water deprivation in vivo as well as the effect of uromodulin on the activity of the water channel aquaporin-2 (AQP2) in vitro and in vivo using transgenic mice. Water deprivation upregulated uromodulin production; immunofluorescence experiments revealed uromodulin adhesion on the apical surface of the collecting duct. Furthermore, the activation of AQP2 was attenuated in mice lacking uromodulin. Uromodulin enhanced the phosphorylation and apical trafficking of AQP2 in mouse collecting duct cells treated with the vasopressin analog dDAVP. The uromodulin-induced apical trafficking of AQP2 was attenuated via endocytosis inhibitor treatment, suggesting that uromodulin activates AQP2 through the suppression of endocytosis. This study provides novel insights into the cross-talk between TAL and the collecting duct, and indicates that the modulation of uromodulin is a promising approach for diuresis and hypertension treatment.

Serum Activin A Is a Novel Biomarker of Endoscopic Activity in Ulcerative Colitis.

Background: Endoscopic healing (EH) is the long-term therapeutic goal for ulcerative colitis (UC). Since repeated colonoscopies are inconvenient and invasive, a surrogate biomarker for endoscopic activity is needed. Activin A is one of the transforming growth factor-ß superfamily of proteins and has been shown to be associated with intestinal inflammation. Methods: This single-center observational study included 27 Japanese patients with UC in clinical remission who underwent colonoscopy and blood sampling. We investigated the correlations between laboratory parameters, including serum activin A levels, and endoscopic activity, classified by the Mayo endoscopic subscore (MES) in these patients. Results: This study included 15 males and 12 females. The median age was 44.0 years. In terms of endoscopic activity, five patients were diagnosed with MES 0, 14 patients with MES 1, seven patients with MES 2, and one patient with MES 3. The median serum activin level was 134.8 pg/mL (interquartile range (IQR), 105.3 - 188.1). Serum activin A levels were significantly correlated with the MES (Spearman's rank correlation coefficient r = 0.591, P = 0.001), which was better than that of C-reactive protein (CRP) (r = 0.487, P = 0.010). In the comparison between the EH group (MES 0) and non-EH group (MES 1-3), patients without EH had significantly higher serum activin A levels (Mann-Whitney U test, P = 0.047). A cutoff value of 133.6 pg/mL indicated non-EH with a sensitivity and specificity of 0.682 and 1.000, respectively. The area under the curve (AUC) of serum activin A for detecting non-EH was 0.791 (95% confidence interval (CI), 0.618 - 0.964), while that of CRP was 0.723 (95% CI, 0.504 - 0.941). Conclusions: The serum activin A level is a potential novel biomarker of endoscopic activity in UC.

Pyloric Incompetence Associated with Helicobactor pylori Infection and Correlated to the Severity of Atrophic Gastritis.

Duodenogastric reflux (DGR) causes bile reflux gastritis (BRG) and may develop into gastric cancer. DGR is classified as primary in non-operated stomachs or secondary to surgical intervention. Primary DGR and Helicobacter pylori (H. pylori) infection are reportedly related. However, the mechanism is not fully understood. This study aimed to elucidate the relationship between H. pylori infection and pyloric incompetence in a non-operated stomach. A total of 502 non-operated participants who underwent an upper intestinal endoscopy were prospectively enrolled. Endoscopic findings (EAC, endoscopic atrophy classification; nodular gastritis; xanthoma; fundic gland polyp; and incompetence of pylorus), sex, age, gastrin, pepsinogen (PG) I and PG II levels were evaluated. PG I/PG II ratio, anti-H. pylori-Ab positivity, and atrophic gastritis status were significantly different between the normal and incompetent pylori (p = 0.043, <0.001, and 0.001, respectively). Open-type atrophic gastritis was significantly higher in the incompetent pylori. Incompetence of the pylorus and EAC were moderately correlated (Cramer's V = 0.25). Multivariate analysis revealed that the presence of anti-H. pylori-Ab was the only independent factor associated with the incompetence of the pylorus, with an adjusted odds ratio of 2.70 (95% CI: 1.47−4.94, p = 0.001). In conclusion, pyloric incompetence was associated with H. pylori infection and moderately correlated to the severity of atrophic gastritis in non-operated stomachs.