Dietary salt intake has been linked to hypertension and cardiovascular disease. Accumulating evidence has indicated that salt-sensitive individuals on high salt intake are more likely to develop renal fibrosis. Epithelial-to-mesenchymal transition (EMT) participates in the development and progression of renal fibrosis in humans and animals. The objective of this study was to investigate the impact of a high-salt diet on EMT in Dahl salt-sensitive (SS) rats. Twenty-four male SS and consomic SS-13BN rats were randomized to a normal diet or a high-salt diet. After 4 weeks, systolic blood pressure (SBP) and albuminuria were analyzed, and renal fibrosis was histopathologically evaluated. Tubular EMT was evaluated using immunohistochemistry and real-time PCR with E-cadherin and alpha smooth muscle actin (α-SMA). After 4 weeks, SBP and albuminuria were significantly increased in the SS high-salt group compared with the normal diet group. Dietary salt intake induced renal fibrosis and tubular EMT as identified by reduced expression of E-cadherin and enhanced expression of α-SMA in SS rats. Both blood pressure and renal interstitial fibrosis were negatively correlated with E-cadherin but positively correlated with α-SMA. Salt intake induced tubular EMT and renal injury in SS rats, and this relationship might depend on the increase in blood pressure.
Accumulating evidence has suggested that high salt and potassium might be associated with vascular function. The aim of this study was to investigate the effect of salt intake and potassium supplementation on brachial-ankle pulse wave velocity (PWV) in Chinese subjects. Forty-nine subjects (28-65 years of age) were selected from a rural community of northern China. All subjects were sequentially maintained on a low-salt diet for 7 days (3.0 g/day NaCl), a high-salt diet for an additional 7 days (18.0 g/day NaCl), and a high-salt diet with potassium supplementation for a final 7 days (18.0 g/day NaCl+4.5 g/day KCl). Brachial-ankle PWV was measured at baseline and on the last day of each intervention. Blood pressure levels were significantly increased from the low-salt to high-salt diet, and decreased from the high-salt diet to high-salt plus potassium supplementation. Baseline brachial-ankle PWV in salt-sensitive subjects was significantly higher than in salt-resistant subjects. There was no significant change in brachial-ankle PWV among the 3 intervention periods in salt-sensitive, salt-resistant, or total subjects. No significant correlations were found between brachial-ankle PWV and 24-h sodium and potassium excretions. Our study indicates that dietary salt intake and potassium supplementation, at least in the short term, had no significant effect on brachial-ankle PWV in Chinese subjects.
Background:D-0120 is a novel oral selective uric acid transporter (URAT1) inhibitor being developed for the treatment of hyperuricemia and gout by blocking the reabsorption of uric acid (UA) within the renal proximal tubule, thereby reducing serum uric acid concentrations. As a novel URAT1 inhibitor, D-0120 is anticipated to have more potent serum UA reducing effect than the approved URAT1 inhibitor lesinurad, but with less toxicity and wider therapeutic window. The pharmacological potential of D-0120 for the treatment of hyperuricemia and gout was demonstrated in preclinical studies. The results of the in vitro hURAT1 expressed CHO cell model showed that the inhibitory activity of D-0120 is 150-fold more potent than lesinurad and slightly more potent than verinurad.Objectives:The purpose of this dose escalation study is to evaluate the safety and tolerability of D-0120 in multiple ascending doses in healthy volunteer, to characterize the pharmacokinetics (PK) of D-0120 and to assess pharmacodynamic (PD) effects and determine the drug-drug interaction (DDI) effect of febuxostat and D-0120 in healthy volunteers.Methods:This is a randomized, double blind, multiple ascending doses Phase I study of D-0120 in healthy volunteers conducted at one site. Thirty-two healthy eligible volunteers with serum uric acid level ≥ 4.5 mg/dL but within normal range at screening were enrolled and dosed with D-0120 within 4 different single agent cohorts for a period of 7 days. Each cohort had 8 subjects randomized at 3:1 ratio for D-0120:placebo. A fifth cohort of 8 healthy eligible volunteers were enrolled and dosed with 5 mg of D-0120 in combination with 40 mg of febuxostat over a period of 9 days. Evaluation of safety, PK and PD was conducted at various timepoints while the patients were in confinement. Further safety evaluation took place on Day 14. A Safety Review Committee reviewed safety, PK and PD data for each cohort of D-0120 dose level (2.5 mg, 5 mg, 10 mg, 20 mg) as well as when D-0120 5 mg was combined with 40 mg febuxostat. PK evaluation for multiple dose parameters included AUC0-τ, Cmax, Cmin, Tmax and Fl.Results:Dose escalation of D-0120 from 2.5 mg/day to 20 mg/day was completed without any dose limiting toxicities. Most AEs occurred during the study were mild to moderate in severity and did not require any treatment before resolution. There was no SAE and no dose reduction during the treatment period. The pharmacokinetic (PK) evaluation of ascending dose levels of D-0120 suggested a dose proportional increase in drug exposure and there was no significant change of PK profile between Day 1 and Day 7 of dosing. For pharmacodynamic (PD) evaluation, the serum uric acid (UA) levels before and after D-0120 dosing was evaluated on multiple days. The UA reduction effect achieved maximum at about 4-8 hours after dosing and the effect lasted for at least 24 hours. After the 7-day dosing period, the mean percentage of UA reduction from baseline showed an increasing trend as the dose level increased.More detailed safety, PK and PD data from multiple D-0120 dose cohorts and D-0120/febuxostat combination cohort will be presented at the meeting.Conclusion:The oral daily administration of a novel URAT1 inhibitor, D-0120, in healthy volunteers for 7 days was well tolerated at dose levels from 2.5 mg/day to 20 mg/day. The PK profile demonstrated a dose proportional increase. D-0120 administration for 7 days resulted in significant reduction of serum UA levels. Further evaluation of this novel agent in longer treatment period and in patients with hyperuricemia and/or gout is warranted.References:Not Applicable.Disclosure of Interests:Ling Zhang Employee of: INVENTISBIO, David Wyatt: None declared, Kathryn Stazzone Employee of: INVENTISBIO, Zhe Shi Employee of: INVENTISBIO, Yaolin Wang Employee of: INVENTISBIO
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.