Research Article: Generation and phenotypic characterization of Pde1a mutant mice

Date Published: July 27, 2017

Publisher: Public Library of Science

Author(s): Xiaofang Wang, Satsuki Yamada, Wells B. LaRiviere, Hong Ye, Jason L. Bakeberg, María V. Irazabal, Fouad T. Chebib, Jan van Deursen, Peter C. Harris, Caroline R. Sussman, Atta Behfar, Christopher J. Ward, Vicente E. Torres, Giovanna Valenti.

http://doi.org/10.1371/journal.pone.0181087

Abstract

It has been proposed that a reduction in intracellular calcium causes an increase in intracellular cAMP and PKA activity through stimulation of calcium inhibitable adenylyl cyclase 6 and inhibition of phosphodiesterase 1 (PDE1), the main enzymes generating and degrading cAMP in the distal nephron and collecting duct, thus contributing to the development and progression of autosomal dominant polycystic kidney disease (ADPKD). In zebrafish pde1a depletion aggravates and overexpression ameliorates the cystic phenotype. To study the role of PDE1A in a mammalian system, we used a TALEN pair to Pde1a exon 7, targeting the histidine-aspartic acid dipeptide involved in ligating the active site Zn++ ion to generate two Pde1a null mouse lines. Pde1a mutants had a mild renal cystic disease and a urine concentrating defect (associated with upregulation of PDE4 activity and decreased protein kinase A dependent phosphorylation of aquaporin-2) on a wild-type genetic background and aggravated renal cystic disease on a Pkd2WS25/- background. Pde1a mutants additionally had lower aortic blood pressure and increased left ventricular (LV) ejection fraction, without a change in LV mass index, consistent with the high aortic and low cardiac expression of Pde1a in wild-type mice. These results support an important role of PDE1A in the renal pathogenesis of ADPKD and in the regulation of blood pressure.

Partial Text

Autosomal dominant polycystic kidney disease (ADPKD) is the fourth leading cause of end-stage kidney disease. It is caused by mutations in PKD1 or PKD2 encoding polycystin 1 and polycystin 2 [1, 2]. Substantial evidence supports the hypothesis that disruption of polycystin function results in dysregulation of intracellular calcium dynamics and upregulation of 3′,5′-cyclic adenosine monophosphate (cAMP) and protein kinase A (PKA) signaling [3–5]. The identification of cAMP and PKA signaling as a therapeutic target [6–9] has led to clinical trials of vasopressin V2 receptor (V2R) antagonists and somatostatin analogs [10, 11] and to the recent approval of the V2R antagonist, tolvaptan, for the treatment of ADPKD with rapidly progressive renal disease in Japan, Canada, the European Union, Switzerland and South Korea.

The Mayo Clinic Institutional Animal Care and Utilization Committee approved all experimental protocols for the work described within this report.

A substantial body of evidence indicates that cAMP and PKA signaling play a central role in PKD [3–5]. It has been proposed that a reduction in intracellular calcium causes the upregulation of cAMP and PKA through stimulation of calcium inhibitable adenylyl cyclase 6 and inhibition of PDE1, the main enzymes generating and degrading cAMP in the distal nephron and collecting duct [6]. Consistent with this hypothesis, a collecting duct-specific knockout of adenylyl cyclase 6 affords protection in a Pkd1 mouse model [24]. Since capacity for hydrolysis of cyclic nucleotides by PDEs far exceeds that for synthesis by adenylyl cyclases [25], modulation of PDE activity, particularly PDE1 activity, may be crucial in PKD.

 

Source:

http://doi.org/10.1371/journal.pone.0181087

 

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