Hydrochlorothiazide ameliorates polyuria caused by tolvaptan treatment of polycystic kidney disease in PCK rats.
Animals
Antidiuretic Hormone Receptor Antagonists
/ adverse effects
Aquaporin 2
/ metabolism
Blood Pressure
/ drug effects
Diuretics
/ therapeutic use
Drug Therapy, Combination
Gene Expression
/ drug effects
Glomerular Filtration Rate
Hydrochlorothiazide
/ therapeutic use
Male
Nitric Oxide Synthase Type I
/ genetics
Polycystic Kidney Diseases
/ drug therapy
Polyuria
/ chemically induced
Prostaglandin-E Synthases
/ genetics
RNA, Messenger
/ metabolism
Rats
Renin
/ genetics
Tolvaptan
/ adverse effects
Urine
Antidiuretics
Diabetes insipidus
Glomerular filtration rate
V2 receptor antagonist
Journal
Clinical and experimental nephrology
ISSN: 1437-7799
Titre abrégé: Clin Exp Nephrol
Pays: Japan
ID NLM: 9709923
Informations de publication
Date de publication:
Apr 2019
Apr 2019
Historique:
received:
16
03
2018
accepted:
29
10
2018
pubmed:
15
11
2018
medline:
30
7
2019
entrez:
15
11
2018
Statut:
ppublish
Résumé
Tolvaptan is an effective treatment for polycystic kidney disease (PKD), but also causes unfortunate polyuria. Hydrochlorothiazide (HCTZ) has been shown to reduce urine volume in nephrogenic diabetes insipidus, raising the possibility that HCTZ could also be effective in reducing tolvaptan-induced polyuria. In this study, we examined the combined administration of HCTZ and tolvaptan. Male PCK rats were divided into four groups of normal chow (Cont), normal chow plus tolvaptan, gavage HCTZ treatment, and tolvaptan + HCTZ. Biochemical examinations of the plasma and urine were performed as well as histological and molecular (mRNA and protein expression) analyses. Groups treated with tolvaptan had significantly higher 24 h urine excretion, which was significantly reduced in the tolvaptan + HCTZ group after 2 weeks. Cyst size, pERK protein expression, and Cyclin D1 mRNA expression were all significantly reduced in both the tolvaptan and tolvaptan + HCTZ groups, indicating that HCTZ did not affect the beneficial functions of tolvaptan. Notably, aquaporin 2 redistribution from the apical to intracellular domains was observed in tolvaptan-treated rats and was partially reversed in the tolvaptan + HCTZ group. The renal glomerular filtration rate was reduced in the tolvaptan + HCTZ group. Significantly lowered mRNA expression of neuronal nitric oxide synthase, prostaglandin E synthase 2 and renin were also found in the medulla, but not in the cortex. HCTZ reduces tolvaptan-induced polyuria without altering its beneficial effects on PKD. This novel therapeutic combination could potentially lead to better PKD treatments and improved quality of life for the affected patients.
Sections du résumé
BACKGROUND
BACKGROUND
Tolvaptan is an effective treatment for polycystic kidney disease (PKD), but also causes unfortunate polyuria. Hydrochlorothiazide (HCTZ) has been shown to reduce urine volume in nephrogenic diabetes insipidus, raising the possibility that HCTZ could also be effective in reducing tolvaptan-induced polyuria. In this study, we examined the combined administration of HCTZ and tolvaptan.
METHODS
METHODS
Male PCK rats were divided into four groups of normal chow (Cont), normal chow plus tolvaptan, gavage HCTZ treatment, and tolvaptan + HCTZ. Biochemical examinations of the plasma and urine were performed as well as histological and molecular (mRNA and protein expression) analyses.
RESULTS
RESULTS
Groups treated with tolvaptan had significantly higher 24 h urine excretion, which was significantly reduced in the tolvaptan + HCTZ group after 2 weeks. Cyst size, pERK protein expression, and Cyclin D1 mRNA expression were all significantly reduced in both the tolvaptan and tolvaptan + HCTZ groups, indicating that HCTZ did not affect the beneficial functions of tolvaptan. Notably, aquaporin 2 redistribution from the apical to intracellular domains was observed in tolvaptan-treated rats and was partially reversed in the tolvaptan + HCTZ group. The renal glomerular filtration rate was reduced in the tolvaptan + HCTZ group. Significantly lowered mRNA expression of neuronal nitric oxide synthase, prostaglandin E synthase 2 and renin were also found in the medulla, but not in the cortex.
CONCLUSION
CONCLUSIONS
HCTZ reduces tolvaptan-induced polyuria without altering its beneficial effects on PKD. This novel therapeutic combination could potentially lead to better PKD treatments and improved quality of life for the affected patients.
Identifiants
pubmed: 30426292
doi: 10.1007/s10157-018-1669-9
pii: 10.1007/s10157-018-1669-9
doi:
Substances chimiques
Antidiuretic Hormone Receptor Antagonists
0
Aqp2 protein, rat
0
Aquaporin 2
0
Diuretics
0
RNA, Messenger
0
Hydrochlorothiazide
0J48LPH2TH
Tolvaptan
21G72T1950
Nitric Oxide Synthase Type I
EC 1.14.13.39
Renin
EC 3.4.23.15
Prostaglandin-E Synthases
EC 5.3.99.3
Types de publication
Journal Article
Langues
eng
Pagination
455-464Subventions
Organisme : Japan Society for the Promotion of Science
ID : 23659438
Organisme : Japan Society for the Promotion of Science
ID : 25860156
Organisme : Japan Society for the Promotion of Science
ID : 26670424
Organisme : Japan Society for the Promotion of Science
ID : 15K18694
Organisme : Japan Society for the Promotion of Science
ID : 15H04834
Organisme : Japan Society for the Promotion of Science
ID : 16H05312
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