Objective: Chronic kidney disease caused by metabolic syndrome (MetS) is characterized by proteinuria, Na retention and hypertension. In the setting of proteinuria, plasminogen/plasmin filtered through damaged glomeruli could activate the epithelial Na channel (ENaC) leading to hypertension, independently of aldosterone. In this study, we evaluated effects of a synthetic serine protease (SP) inhibitor, camostat mesilate (CM) which inhibits the plasmin activity, on salt-sensitive hypertension in a rat model of MetS with high-salt (HS) diet. In addition, we studied protective effects of CM against podocyte injury in vitro. Design and Method: Five-week-old SHR and control WKY were divided into WKY, SHR, and SHR + CM (Experiment 1), and 13-week-old SHR/ND mcr-cp (model rats for MetS) were divided into normal chow (NS), HS (8.0% NaCl diet), and HS + CM (Experiment 2). After systolic BP measurement and 24 h urine collection were performed for 4 weeks, rats were sacrificed for histological examination. Urinary plasmin activities were evaluated by zymography. Cultured murine podocytes in high aldosterone and glucose media were treated with CM. Results: In Experiment 1, although SHR displayed hypertension, urinary protein excretion and plasmin activity were not substantially increased. Accordingly, CM did not prevent hypertension in SHR (SBP (mmHg): SHR 162 vs. SHR + CM 158). In Experiment 2, HS diet induced severe hypertension, marked proteinuria and plasmin activation in urine in SHR/ND mcr-cp. These changes were significantly suppressed by the treatment with CM (SBP (mmHg): HS 230 vs. HS + CM 178). CM increased urinary sodium/potassium ratio, indicating that CM inhibited the ENaC activity. Although CM mitigated apoptosis of podocytes in vivo and in vitro, CM did not inhibit the activity of Omi/HtrA2 that is a mitochondrial SP associated with apoptosis. Conclusions: In conclusion, CM could exert significant antihypertensive and renoprotective effects in a rat model of MetS, suggesting that SP inhibition could be a new therapeutic strategy against salt-sensitive hypertension in MetS.
Over 170 types of chemical modifications have been identified in cellular RNAs across the three domains of life. Modified RNA is eventually degraded to constituent nucleosides, and in mammals, modified nucleosides are released into the extracellular space. By contrast, the fate of modified nucleosides in bacteria remains unknown. In this study, we performed liquid chromatography-mass spectroscopy (LC-MS) analysis of modified nucleosides from the RNA of 23 pathogenic bacteria, revealing 2-methyladenosine (m
<b><i>Background/Aims:</i></b> We have so far demonstrated the renoprotective effect of camostat mesilate (CM) in 5/6 nephrectomized rats at least partly through its antioxidant effect. However, precise mechanisms were not fully clarified. Therefore, we now examined the renoprotective and antioxidant mechanisms of CM by using the adenine-induced chronic kidney disease (CKD) rat model. <b><i>Methods:</i></b> In <i>protocol 1</i>, we analyzed the effect of CM on CKD. Rats were fed on a 0.75% adenine diet for 3 weeks to induce CKD followed by the experimental period with vehicle, CM, or hydralazine (HYD) treatment for 5 weeks. In <i>protocol 2</i>, we examined the safety of CM and HYD on the normal rats. In addition, we explored free radical scavenging activities of CM and its metabolites in vitro using electron paramagnetic resonance (EPR) spectroscopy. <b><i>Results:</i></b> CM, but not HYD, significantly reduced the serum creatinine levels, although both treatments showed similar reduction in the blood pressure. CM decreased mRNA expression and protein levels of fibrotic markers, the severity of renal fibrosis, the accumulation of oxidative stress, and the expression of NADPH oxidase components in the kidney. In the <i>protocol 2</i>, there were no statistically significant differences in general parameters except for the systolic blood pressure in HYD group. EPR study revealed that CM and its metabolites have potent hydroxyl radical scavenging activities in vitro. <b><i>Conclusion:</i></b> Our findings indicate that CM significantly ameliorates the progression of CKD partly through its antioxidant effect independently from its blood pressure-lowering effect. Our results suggest the possibility that CM could be a new therapeutic agent that could arrest the progression of CKD.
Prader-Willi syndrome is rather a rare disease. However, as it includes 4 features (hypogonadism, hypomentia, hypotonia, and obesity), urologist may see the patients with this syndrome for their gonadal problem. We studied all the 27 cases in our hospital of which data were precisely collected. Among males, 67% of patients had presented themselves first to the department of pediatric internal medicine. One third of the patients were not diagnosed as the syndrome and referred to our clinic because of urological abnormalities. Chromosomal abnormality was seen in 40.9%. We found cryptorchism in all the cases and micropenis in 56%. In females, delayed menarche over 15-year-old was seen in 75%. From endocrinological studies, 75% male showed low reaction against HCG stimulation. Low gonadotropin responses to LH-RH were seen in 80% of all patients. We performed orohiopexy for cryptorchism, but testicular development was poor. And we do not actively ulilize hormonal therapies for these patients.
Abstract Background Malnutrition is associated with discontinuing peritoneal dialysis (PD). The prognostic nutritional index (PNI), composed of serum albumin level and total lymphocyte count, has been suggested as a prognostic marker for mortality in patients undergoing PD. However, the relationship between PNI and PD discontinuation has not yet been well addressed. We evaluated the relationship between PNI and PD discontinuation in patients with end-stage kidney disease who initiated PD treatment. Methods This retrospective cohort study included patients who underwent PD at a single academic hospital between 2007 and 2022. We examined the association between PNI (< 40 vs. ≥ 40) and PD discontinuation using Cox proportional hazards regression models. We used restricted cubic spline analysis to examine the continuous associations between the PNI and outcomes. Results The mean age (and standard deviation) of the 91 patients was 57.1 ± 13.4 years; 72 (79.1%) discontinued PD during the median follow-up period of 25.0 months. Lower PNI was associated with an increased risk of PD discontinuation. The hazard ratios (95% confidence intervals) with three levels of adjustments were 1.74 (1.08, 2.79), 2.21 (1.32, 3.66), and 1.81 (1.01, 3.24) (reference: PNI ≥ 40). Restricted cubic spline analysis showed that a PNI < 40 was continuously associated with a higher risk of PD discontinuation. Conclusion A lower PNI (< 40) was associated with a higher risk of PD discontinuation. Our findings suggest that evaluating the PNI may help identify patients at high risk of PD discontinuation and lead to appropriate nutritional management for dialysis maintenance.
Serine proteases (SPs) play physiological roles in the kidney. We previously reported that a synthetic SP inhibitor, camostat mesilate (CM), suppressed sodium reabsorption in the renal tubule and showed natriuretic effects in aldosterone-infused rats. Here, we aimed to explore novel physiological roles of SPs in the renal tubule and understand the mechanism of actions of SP inhibitors, by administering CM to healthy rats. Sprague–Dawley rats were classified into control and CM (subcutaneous sustained-release pellet) groups and sacrificed on day 7. CM significantly increased urine volumes by approximately two-fold in a urinary sodium- and osmolyte excretion-independent manner, indicating the occurrence of free water excretion. Serum vasopressin, potassium, and calcium levels and the osmolality in the renal medulla, which all affect free water reabsorption in the renal tubule, remained unchanged after CM administration. CM decreased urinary exosomal AQP2 excretion, suggesting suppression of AQP2 activity in the collecting duct. These changes were reversed by desmopressin infusion. Water diuresis caused by CM was independent of its action on prostasin or TMPRSS4. Our results revealed the association of SP inhibition with free water handling and demonstrated that CM administration exerted diuretic effects with AQP2 downregulation, suggesting SP inhibitors as a new class of aquaretic drugs.
