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Generation and phenotypic characterization of Pde1a mutant mice.

Generation and phenotypic characterization of Pde1a mutant mice.
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Wang X, Yamada S, LaRiviere WB, Ye H, Bakeberg JL, Irazabal MV, Chebib FT, van Deursen J, Harris PC, Sussman CR, Behfar A, Ward CJ, Torres VE,


Wang X, Yamada S, LaRiviere WB, Ye H, Bakeberg JL, Irazabal MV, Chebib FT, van Deursen J, Harris PC, Sussman CR, Behfar A, Ward CJ, Torres VE, (click to view)

Wang X, Yamada S, LaRiviere WB, Ye H, Bakeberg JL, Irazabal MV, Chebib FT, van Deursen J, Harris PC, Sussman CR, Behfar A, Ward CJ, Torres VE,

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PloS one 2017 07 2712(7) e0181087 doi 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.

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