Signaling role of PDE isozymes in pathobiology of glomerular mesangial cells. Studies in vitro and in vivo

Cell Biochemistry and Biophysics
T P Dousa

Abstract

Mesangial cells (MC) of renal glomeruli respond to immune-inflammatory injury by accelerated proliferation and generation of reactive oxygen metabolites (ROM). We studied in vivo and in vitro roles of cAMP-protein kinase A (PKA) signaling in modulation of these pathobiologic processes with focus on PDE isozymes. Mitogenic synthesis of DNA in mesangial cells grown in primary culture was blocked by forskolin and dibutyryl cyAMP. Incubation of MC with PDE-3 inhibitors, cilostamide and lixazinone, inhibited (> 50%) mitogenesis, whereas inhibitors of PDE-4, rolipram and denbufylline, caused little or no inhibition. Conversely, inhibitors of PDE-4 suppressed generation of ROM in MC, whereas inhibitors of PDE-3 had no effect. Incubation of mesangial cells with cilostamide or with rolipram increased in situ activity of PKA, and effects of the two inhibitors were additive. PDE inhibitors also decreased activity of mitogen-activated protein kinase. The efficacy of PDE isozyme inhibitors (IC50) to suppress mitogenesis or ROM generation paralleled IC50 for inhibition of cAMP hydrolysis by extracts from mesangial cells. Administration of lixazinone or lixazinone in combination with rolipram to rats with mesangial proliferative glomeruloneph...Continue Reading

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Citations

Nov 28, 2012·European Journal of Clinical Pharmacology·Zahra Nasiri-ToosiMahboob Lessan-Pezeshki
Jul 4, 2008·Nephrology, Dialysis, Transplantation : Official Publication of the European Dialysis and Transplant Association - European Renal Association·Bernd HohensteinChristian Hugo
Dec 4, 2012·Nephrology, Dialysis, Transplantation : Official Publication of the European Dialysis and Transplant Association - European Renal Association·Lilla FangGábor Kökény
Feb 13, 2009·Renal Failure·Mehmet Kaya OzerEkrem Cicek
Apr 9, 2005·Journal of the Chinese Medical Association : JCMA·Shuei-Liong LinBor-Shen Hsieh
Jun 6, 2006·British Journal of Pharmacology·Ying ZhuMasanori Kitamura

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