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.
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