Cyclic AMP increases rat inhibitor of apoptosis protein (RIAP1) mRNA in renal mesangial cells.

Abstract

The cyclic adenosine 3',5'-monophosphate (cAMP) pathway plays a central role in the regulation of cell proliferation, differentiation and apoptosis. Cyclic AMP has been identified as a bifunctional regulator of apoptosis. The inhibitor of apoptosis proteins (IAP) regulates apoptosis by directly inhibiting distinct caspases. Expression levels of rat IAP (RIAP)-1 were investigated by RNase protection assay in rat mesangial cells after stimulation with diverse agents that modulate cellular levels of cAMP. Rat mesangial cells up-regulated RIAP1 mRNA levels after cAMP stimulation. Membrane-permeable cAMP analogs, as well as cAMP production in response to the beta-adrenergic receptor agonist salbutamol caused a large increase in RIAP1 mRNA level, which could be inhibited by the protein kinase A inhibitors H89 and Rp-cAMPS, or by the nuclear factor-kappaB (NF-kappaB) inhibitor BAY117085. Inhibition of phosphodiesterase type IV by denbufyllin or rolipram potentiated the cAMP-mediated increase in RIAP1 mRNA. In contrast, the cyclic guanosine 3',5'-monophosphate (cGMP) analog Bt2cGMP did not affect the RIAP1 mRNA level. These data establish, to our knowledge for the first time, that RIAP1 mRNA levels are regulated by the cAMP-signaling pathway and suggest potential new avenues of therapy to modulate apoptosis.