Inhibitors of cyclic nucleotide phosphodiesterase isozymes block renal tubular cell proliferation induced by folic acid
| Autor: | Thomas P. Dousa, Yasushi Tsuboi, Karel Matousovic, Joseph P. Grande, Henry J. Walker |
|---|---|
| Rok vydání: | 1997 |
| Předmět: |
Male
Phosphodiesterase Inhibitors Phosphodiesterase 3 Down-Regulation Tetrazoles Biology Quinolones Isozyme Pathology and Forensic Medicine Rats Sprague-Dawley chemistry.chemical_compound Folic Acid Proliferating Cell Nuclear Antigen medicine Cyclic AMP Animals Cyclic adenosine monophosphate Protein kinase A Cyclic guanosine monophosphate Rolipram Phosphodiesterase General Medicine Molecular biology Cyclic AMP-Dependent Protein Kinases Cyclic Nucleotide Phosphodiesterases Type 3 Pyrrolidinones Cilostazol Rats Isoenzymes Kidney Tubules chemistry 3' 5'-Cyclic-AMP Phosphodiesterases Quinazolines Signal transduction Cell Division medicine.drug Signal Transduction |
| Zdroj: | The Journal of laboratory and clinical medicine. 130(5) |
| ISSN: | 0022-2143 |
| Popis: | In previous studies we observed that inhibition of cyclic 3′,5′-nucleotide phosphodiesterase (PDE) isozymes, namely isozyme PDE3, suppresses proliferation of rat renal glomerular mesangial cells in vitro and in vivo. To determine whether activation of the cyclic adenosine monophosphate (cAMP)-protein kinase A (PKA) signaling pathway coupled to specific PDE isozymes modulates accelerated proliferation of renal epithelial cells, we investigated the effect of selective PDE isozyme inhibition on renal epithelial cell proliferation induced in rats by injection of folic acid (FA). In extracts from suspensions of renal cortical tubules, cAMP was metabolized predominantly by isozyme PDE4; activity of PDE3 was about three times lower. The increase in proliferative activity of renal cortical tissue from FA-injected rats, evaluated by immunostaining with Mib-1 antibody, was limited to tubular epithelial cells. Administration of the PDE3 inhibitors cilostazol or cilostamide together with the PDE4 inhibitor rolipram blocked mitogenic synthesis of DNA, as determined by ( 3 H)-thymidine incorporation into renal cortical DNA, in FA-treated rats. FA injection caused an increase of more than 10-fold in proliferating cell nuclear antigen (PCNA) in renal cortical tissue; administration of the potent PDE3 inhibitor lixazinone or, to a lesser degree, cilostazol suppressed these high PCNA levels, whereas rolipram alone had no effect. The results indicate that FA-stimulated in vivo proliferation of renal tubular epithelial cells is down-regulated by activation of a cAMPPKA signaling pathway linked to PDE3 isozymes. These observations are consistent with the notion that negative crosstalk between cAMP signaling and mitogenstimulated signaling pathways regulates mitogenesis of renal cells of different terminal differentiation, including tubular epithelial cells. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full Text from ScienceDirect