ArticleKidney international2015
Salt-sparing diuretic action of a water-soluble urea analog inhibitor of urea transporters UT-A and UT-B in rats.
Article in Kidney international, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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Who cites it
16 citing papers in PubMed, 25 citations in OpenAlex.
- Time-Restricted Feeding With High-Fat Diet Slows Weight Gain and Reduces Renal Calcium Oxalate Crystal Formation Without Reducing Energy Intake.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2026Article
- Epithelial plasma membrane transporters as drug targets.Physiological reviews · 2026Review
- The Physiological Roles and Pathological Implications of Urea Transporters in the Cardiovascular System.Biomedicines · 2025Review
- Small-Molecule Inhibitors and Drug Discovery of Urea Transporters.Sub-cellular biochemistry · 2025Review
- Blood pressure alteration associated with abnormal body electrolyte and water balance in colitis mice.Hypertension research : official journal of the Japanese Society of Hypertension · 2024Article
- Aquaporins in Cardiovascular System.Advances in experimental medicine and biology · 2023Article
- A critical analysis of urea transporter B inhibitors: molecular fingerprints, pharmacophore features for the development of next-generation diuretics.Molecular diversity · 2022Article
- Identification of sodium homeostasis genes in Camelus bactrianus by whole transcriptome sequencing.FEBS open bio · 2022Article
- Mechanisms and management of edema in pediatric nephrotic syndrome.Pediatric nephrology (Berlin, Germany) · 2021Review
- Discovery of novel diarylamides as orally active diuretics targeting urea transporters.Acta pharmaceutica Sinica. B · 2021Article
- Nanomolar-Potency 1,2,4-Triazoloquinoxaline Inhibitors of the Kidney Urea Transporter UT-A1.Journal of medicinal chemistry · 2018Article
- Emerging Targets of Diuretic Therapy.Clinical pharmacology and therapeutics · 2017Review
- Small-Molecule Inhibitors of Pendrin Potentiate the Diuretic Action of Furosemide.Journal of the American Society of Nephrology : JASN · 2016Article
- Urea transport and clinical potential of urearetics.Current opinion in nephrology and hypertension · 2016Review
- Phenylphthalazines as small-molecule inhibitors of urea transporter UT-B and their binding model.Acta pharmacologica Sinica · 2016Article
- Structure-activity analysis of thiourea analogs as inhibitors of UT-A and UT-B urea transporters.Biochimica et biophysica acta · 2015Article
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Authors and funding
8 authors at 3 institutions in 2 countries.
Funding
Abstract
Inhibitors of kidney urea transporter (UT) proteins have potential use as salt-sparing diuretics ('urearetics') with a different mechanism of action than diuretics that target salt transporters. To study UT inhibition in rats, we screened about 10,000 drugs, natural products and urea analogs for inhibition of rat UT-A1. Drug and natural product screening found nicotine, sanguinarine and an indolcarbonylchromenone with IC50 of 10-20 μM. Urea analog screening found methylacetamide and dimethylthiourea (DMTU). DMTU fully and reversibly inhibited rat UT-A1 and UT-B by a noncompetitive mechanism with IC50 of 2-3 mM. Homology modeling and docking computations suggested DMTU binding sites on rat UT-A1. Following a single intraperitoneal injection of 500 mg/kg DMTU, peak plasma concentration was 9 mM with t1/2 of about 10 h, and a urine concentration of 20-40 mM. Rats chronically treated with DMTU had a sustained, reversible reduction in urine osmolality from 1800 to 600 mOsm, a 3-fold increase in urine output, and mild hypokalemia. DMTU did not impair urinary concentrating function in rats on a low protein diet. Compared to furosemide-treated rats, the DMTU-treated rats had greater diuresis and reduced urinary salt loss. In a model of syndrome of inappropriate antidiuretic hormone secretion, DMTU treatment prevented hyponatremia and water retention produced by water-loading in dDAVP-treated rats. Thus, our results establish a rat model of UT inhibition and demonstrate the diuretic efficacy of UT inhibition.
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