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2014 ; 25
(10
): 2222-30
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Phosphodiesterase 1A modulates cystogenesis in zebrafish
#MMPMID24700876
Sussman CR
; Ward CJ
; Leightner AC
; Smith JL
; Agarwal R
; Harris PC
; Torres VE
J Am Soc Nephrol
2014[Oct]; 25
(10
): 2222-30
PMID24700876
show ga
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.
|Amino Acid Sequence
[MESH]
|Animals
[MESH]
|Cyclic AMP/*metabolism
[MESH]
|Cyclic Nucleotide Phosphodiesterases, Type 1/*metabolism
[MESH]
free
free
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