Generation and phenotypic characterization of Pde1a mutant mice.
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 an...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2017-01-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC5531505?pdf=render |
| _version_ | 1819240223170625536 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Xiaofang Wang |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-23T14:04:36Z |
| format | Article |
| id | doaj.art-4881d5fd0089430daf7a06705af5381c |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-23T14:04:36Z |
| publishDate | 2017-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-4881d5fd0089430daf7a06705af5381c2022-12-21T17:44:12ZengPublic Library of Science (PLoS)PLoS ONE1932-62032017-01-01127e018108710.1371/journal.pone.0181087Generation and phenotypic characterization of Pde1a mutant mice.Xiaofang WangSatsuki YamadaWells B LaRiviereHong YeJason L BakebergMaría V IrazabalFouad T ChebibJan van DeursenPeter C HarrisCaroline R SussmanAtta BehfarChristopher J WardVicente E TorresIt 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.http://europepmc.org/articles/PMC5531505?pdf=render |
| spellingShingle | 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 Generation and phenotypic characterization of Pde1a mutant mice. PLoS ONE |
| title | Generation and phenotypic characterization of Pde1a mutant mice. |
| title_full | Generation and phenotypic characterization of Pde1a mutant mice. |
| title_fullStr | Generation and phenotypic characterization of Pde1a mutant mice. |
| title_full_unstemmed | Generation and phenotypic characterization of Pde1a mutant mice. |
| title_short | Generation and phenotypic characterization of Pde1a mutant mice. |
| title_sort | generation and phenotypic characterization of pde1a mutant mice |
| url | http://europepmc.org/articles/PMC5531505?pdf=render |
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