Effect of a Vasopressin V2 Receptor Antagonist on Polycystic Kidney Disease Development in a Rat Model

Xiaofang Wang, Megan M. Constans, Fouad Chebib, Vicente Torres, Lorenzo Pellegrini

Research output: Contribution to journalArticle

Abstract

Background: Vasopressin V2 receptor inhibition is a clinically validated mechanism of action in the treatment of autosomal dominant polycystic kidney disease (ADPKD). In this study, the effect of lixivaptan, a potent, selective vasopressin V2 antagonist, was evaluated in PCK rats, a validated animal model of PKD. Methods: Four-week old PCK rats were fed rodent chow with 0.5% lixivaptan (low dose) or 1% lixivaptan (high dose), or chow only (control) for 8 weeks. Urine output was measured at weeks 7 and 10 of age. Animals were killed at 12 weeks of age; kidneys and livers were collected, weighted, and analyzed for cyclic adenosine 3′,5′-monophosphate (cAMP) levels and cystic burden and fibrosis; serum creatinine and sodium were measured. Results: Consistent with the development of a polycystic kidney phenotype, control PCK rats showed enlarged kidneys, extensive cyst formation, and early signs of serum creatinine elevation at 12 weeks of age. Compared to controls, PCK rats treated with low-dose lixivaptan showed a 26% reduction in % kidney weight/body weight (p < 0.01); a 54% reduction in kidney cystic score (p < 0.001), a histomorphometric measure of cystic burden; a 23% reduction in kidney cAMP levels (p < 0.05), a biochemical marker of disease; and a 13% reduction in plasma creatinine (p < 0.001), indicating preserved renal function. These reductions were associated with 3-fold increases in 24-h urine output, demonstrating the potent aquaretic effect of lixivaptan. The fact that the high dose was less efficacious than the low dose is discussed. Conclusions: These results provide the first evidence of the potential utility of lixivaptan for the treatment of ADPKD.

Original languageEnglish (US)
Pages (from-to)487-493
Number of pages7
JournalAmerican Journal of Nephrology
Volume49
Issue number6
DOIs
StatePublished - Jun 1 2019

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Vasopressin Receptors
Polycystic Kidney Diseases
Kidney
Autosomal Dominant Polycystic Kidney
Creatinine
Adenosine
Urine
Cystic Kidney Diseases
Serum
Cystic Fibrosis
Antidiuretic Hormone Receptor Antagonists
lixivaptan
Cysts
Rodentia
Animal Models
Biomarkers
Sodium
Body Weight
Phenotype
Weights and Measures

ASJC Scopus subject areas

  • Nephrology

Cite this

Effect of a Vasopressin V2 Receptor Antagonist on Polycystic Kidney Disease Development in a Rat Model. / Wang, Xiaofang; Constans, Megan M.; Chebib, Fouad; Torres, Vicente; Pellegrini, Lorenzo.

In: American Journal of Nephrology, Vol. 49, No. 6, 01.06.2019, p. 487-493.

Research output: Contribution to journalArticle

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AB - Background: Vasopressin V2 receptor inhibition is a clinically validated mechanism of action in the treatment of autosomal dominant polycystic kidney disease (ADPKD). In this study, the effect of lixivaptan, a potent, selective vasopressin V2 antagonist, was evaluated in PCK rats, a validated animal model of PKD. Methods: Four-week old PCK rats were fed rodent chow with 0.5% lixivaptan (low dose) or 1% lixivaptan (high dose), or chow only (control) for 8 weeks. Urine output was measured at weeks 7 and 10 of age. Animals were killed at 12 weeks of age; kidneys and livers were collected, weighted, and analyzed for cyclic adenosine 3′,5′-monophosphate (cAMP) levels and cystic burden and fibrosis; serum creatinine and sodium were measured. Results: Consistent with the development of a polycystic kidney phenotype, control PCK rats showed enlarged kidneys, extensive cyst formation, and early signs of serum creatinine elevation at 12 weeks of age. Compared to controls, PCK rats treated with low-dose lixivaptan showed a 26% reduction in % kidney weight/body weight (p < 0.01); a 54% reduction in kidney cystic score (p < 0.001), a histomorphometric measure of cystic burden; a 23% reduction in kidney cAMP levels (p < 0.05), a biochemical marker of disease; and a 13% reduction in plasma creatinine (p < 0.001), indicating preserved renal function. These reductions were associated with 3-fold increases in 24-h urine output, demonstrating the potent aquaretic effect of lixivaptan. The fact that the high dose was less efficacious than the low dose is discussed. Conclusions: These results provide the first evidence of the potential utility of lixivaptan for the treatment of ADPKD.

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