Angiotensin II (AII) plays a major role in the progression of chronic kidney 
diseases. Podocytes are essential components of the ultrafiltration apparatus, 
and are targets for AII signaling. AII has been shown to increase generation of 
reactive oxygen species (ROS) in podocytes. Canonical transient receptor 
potential-6 (TRPC6) channels stimulate Ca(2+) influx in podocytes, and have been 
implicated in glomerular disease. We observed that AII increased cationic 
currents in rat podocytes in an isolated glomerulus preparation in which 
podocytes are still attached to the underlying capillary. This effect was 
completely blocked by SKF-96365, by micromolar La(3+) , and by siRNA knockdown 
of TRPC6, indicating that TRPC6 is the primary source of Ca(2+) influx mobilized 
by endogenously expressed angiotensin II receptors in these cells. These 
responses were also blocked by the AT1R antagonist losartan, the phospholipase C 
inhibitor D-609, and by inhibition of G protein signaling. The pan-protein 
kinase C inhibitor chelerythrine had no effect. Importantly, pretreating 
podocytes with the ROS quencher manganese (III) tetrakis (4-benzoic acid) 
porphyrin chloride (MnTBAP) eliminated AII activation of TRPC6. Significant 
reductions of AII effects on podocyte TRPC6 were also observed after 
pretreatment with NADPH oxidase inhibitors apocynin or diphenylene iodonium 
(DPI). These data suggest that ROS production permits activation of TRPC6 
channels by G protein and PLC-dependent cascades initiated by AII acting on 
AT1Rs in podocytes. This pathway also provides a basis whereby two forms of 
cellular stress-oxidative stress and Ca(2+) overload-converge on common pathways 
relevant to disease.