Receptor—independent intracellular radical scavenging activity of angiotensin II receptor blocker

Angiotensin II (Ang II) plays a crucial role in induction of oxidative stress and the pathogenesis of cardiovascular and renal disease Beneficial mechanisms of Ang II receptor 1 (ATI) blockers (ARB) are multifactoriaL In order to investigate a receptor independent protective role of ARB, we employed primary-cultured cells from ATI knockout (KO) or wild type (WT) mouse and a highly lipophilic ARB. telmisartan. Intracellular free radicals were estimated by a fluorogenic probe CM-H₂DCFDA. To generate a non-Ang II-induced reactive oxygen species (ROS) production. cells were exposed to hydrogen peroxide (H₂Q₂) alone or after treatment with telmisartan, Flow cytometry analysis showed that Ang II induced a significant increase of ROS production in a dose-dependant manner in WT cells. While Ang II did not increase ROS production in KO cells, H₂H₂induced oxidative stress in both WT and KO cells, Interestingly, telmisartan attenuated oxidative stress induced by H₂O₂in KO cells as well as in WT cells, suggesting a receptor-inde-pendent anti-oxidative effect of telmisartan. In order to study functional consequences of oxidative stress in mesangial cells, we investigated expression of plasminogen activator inhibitor 1 (PAT1). which is stimulated by oxidative stress and plays an important role in renal disease Quantitative analysis of mRNA expression of PAI -1 confirmed attenuation of intracellular ROS production by the ARB via receptor-independent as well as receptor-dependent manner. These results demonstrated that telmisartan inhibited intracellular oxidative stress, at least in part, in a receptor-inde-pendent manner, possibly profiting from its lipophilic and antioxidant structure.