Tolvaptan plus pasireotide shows enhanced efficacy in a PKD1 model

Katharina Hopp, Cynthia J. Hommerding, Xiaofang Wang, Hong Ye, Peter C Harris, Vicente Torres

Research output: Contribution to journalArticle

38 Citations (Scopus)

Abstract

Autosomal dominant polycystic kidney disease (ADPKD) is a leading cause of ESRD. A central defect associated with ADPKD pathology is elevated levels of 3′,5′-cyclic AMP (cAMP). Compounds such as tolvaptan and pasireotide, which indirectly reduce adenylyl cyclase 6 (AC6) activity, have hence proven effective in slowing cyst progression. Here, we tested the efficacy of these compounds individually and in combination in a hypomorphic PKD1 model, Pkd1R3277C/R3277C (Pkd1RC/RC), in a 5-month preclinical trial. Initially, the Pkd1RC/RC model was inbred into the C57BL/6 background, minimizing disease variability, and the pathogenic effect of elevating cAMP was confirmed by treatment with the AC6 stimulant desmopressin. Treatment with tolvaptan or pasireotide alone markedly reduced cyst progression and in combination showed a clear additive effect. Furthermore, combination treatment significantly reduced cystic and fibrotic volume and decreased cAMP to wild-type levels. We also showed that Pkd1RC/RC mice experience hepatic hypertrophy that can be corrected by pasireotide. The observed additive effect reinforces the central role of AC6 and cAMP in ADPKD pathogenesis and highlights the likely benefit of combination therapy for patients with ADPKD.

Original languageEnglish (US)
Pages (from-to)39-47
Number of pages9
JournalJournal of the American Society of Nephrology
Volume26
Issue number1
DOIs
StatePublished - Jan 1 2015

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Autosomal Dominant Polycystic Kidney
Cyclic AMP
Cysts
Deamino Arginine Vasopressin
Therapeutics
Hypertrophy
Chronic Kidney Failure
Pathology
tolvaptan
pasireotide
Liver
adenylyl cyclase 6

ASJC Scopus subject areas

  • Nephrology

Cite this

Tolvaptan plus pasireotide shows enhanced efficacy in a PKD1 model. / Hopp, Katharina; Hommerding, Cynthia J.; Wang, Xiaofang; Ye, Hong; Harris, Peter C; Torres, Vicente.

In: Journal of the American Society of Nephrology, Vol. 26, No. 1, 01.01.2015, p. 39-47.

Research output: Contribution to journalArticle

Hopp, Katharina ; Hommerding, Cynthia J. ; Wang, Xiaofang ; Ye, Hong ; Harris, Peter C ; Torres, Vicente. / Tolvaptan plus pasireotide shows enhanced efficacy in a PKD1 model. In: Journal of the American Society of Nephrology. 2015 ; Vol. 26, No. 1. pp. 39-47.
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