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.
Highlights
Autosomal dominant polycystic kidney disease (ADPKD) is the fourth leading cause of endstage kidney disease
Western blotting with a V5 antibody showed a 64 kDa protein in the oocytes injected with the wild-type or Pde1aDel15 RNA and a truncated 30 kDa protein in oocytes injected with the Pde1aInsA RNA (Fig 1D)
Western blot analysis of kidney lysates from wild-type mice with a PDE1A polyclonal antibody showed a 64 kDa protein, which was markedly reduced in Pde1aDel15 and absent in Pde1aInsA mice (Fig 1F)
Summary
Autosomal dominant polycystic kidney disease (ADPKD) is the fourth leading cause of endstage 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 [3,4,5]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript
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