Phosphodiesterase 1A modulates cystogenesis in zebrafish.
Substantial evidence indicates the importance of elevated cAMP in polycystic kidney disease (PKD). Accumulation of cAMP in cystic tissues may be, in part, caused by enhanced adenylyl cyclase activity, but inhibition of cAMP degradation by phosphodiesterases (PDE) likely has an important role, because cAMP is inactivated much faster than it is synthesized. PDE1 is the only PDE family activated by Ca(2+), which is reduced in PKD cells. To assess the contribution of the PDE1A subfamily to renal cyst formation, we examined the expression and function of PDE1A in zebrafish. We identified two splice isoforms with alternative starts corresponding to human PDE1A1 and PDE1A4. Expression of the two isoforms varied in embryos and adult tissues, and both isoforms hydrolyzed cAMP with Ca(2+)/calmodulin dependence. Depletion of PDE1A in zebrafish embryos using splice- and translation-blocking morpholinos (MOs) caused pronephric cysts, hydrocephalus, and body curvature. Human PDE1A RNA and the PKA inhibitors, H89 and Rp-cAMPS, partially rescued phenotypes of pde1a morphants. Additionally, MO depletion of PDE1A aggravated phenotypes in pkd2 morphants, causing more severe body curvature, and human PDE1A RNA partially rescued pkd2 morphant phenotypes, pronephric cysts, hydrocephalus, and body curvature. Together, these data indicate the integral role of PDE1A and cAMP signaling in renal development and cystogenesis, imply that PDE1A activity is altered downstream of polycystin-2, and suggest that PDE1A is a viable drug target for PKD.
Nephrology and Hypertension, Mayo Clinic College of Medicine, Rochester, Minnesota sussman.carli@mayo.edu.
Caroline R
CR
Sussman
Nephrology and Hypertension, Mayo Clinic College of Medicine, Rochester, Minnesota.
Christopher J
CJ
Ward
Nephrology and Hypertension, Mayo Clinic College of Medicine, Rochester, Minnesota.
Amanda C
AC
Leightner
Nephrology and Hypertension, Mayo Clinic College of Medicine, Rochester, Minnesota.
Jordan L
JL
Smith
Nephrology and Hypertension, Mayo Clinic College of Medicine, Rochester, Minnesota.
Reema
R
Agarwal
Nephrology and Hypertension, Mayo Clinic College of Medicine, Rochester, Minnesota.
Peter C
PC
Harris
Nephrology and Hypertension, Mayo Clinic College of Medicine, Rochester, Minnesota.
Vicente E
VE
Torres
D000595:Amino Acid Sequence; D000818:Animals; D000242:Cyclic AMP / Q000378:metabolism*; D054677:Cyclic Nucleotide Phosphodiesterases, Type 1 / Q000378:metabolism*; D004195:Disease Models, Animal; D004625:Embryo, Nonmammalian / Q000201:enzymology; D006801:Humans; D006849:Hydrocephalus / Q000209:etiology; D007668:Kidney / Q000196:embryology*; D008969:Molecular Sequence Data; D010641:Phenotype; D007690:Polycystic Kidney Diseases / Q000201:enzymology* / Q000209:etiology; D050396:TRPP Cation Channels / Q000378:metabolism; D015027:Zebrafish
D000242:Cyclic AMP; D054677:Cyclic Nucleotide Phosphodiesterases, Type 1; D050396:TRPP Cation Channels