Genetic studies have led to the identification of proteins playing a crucial role in glomerular slit-diaphragm signaling and maintenance of podocyte integrity. Particularly, the gene encoding transient receptor potential canonical channel 6 (TRPC6) was identified as the genetic basis for an autosomal dominant form of focal segmental glomerulosclerosis (FSGS). A key role for podocytes in the pathogenesis of proteinuric diseases has been established since the injury of these cells leads to proteinuria and foot process effacement. Interstitial angiotensin II (Ang II) is found to be a key mediator of renal inflammation and fibrosis in chronic nephropathies. It was shown that expression of Ang II and its receptors (ATRs) is increased in patients with progressive glomerulopathies; what is more, Ang II application can increase intracellular calcium, and members of the TRPC-family channels emerged as prime candidates for this raise. The goal of this research was to define the signaling mechanisms mediating the effect of Ang II on TRPC6 channels in the podocytes and to study the potential capabilities of ATRs inhibitors in the treatment of FSGS. To address this aim we established a new approach allowing to measure ion channels activity and calcium concentration changes in the freshly isolated decapsulated glomeruli. We examined the effects of Ang II on intracellular Ca2+ concentrations in intact podocytes of the rat glomeruli. Changes in intracellular Ca2+ stimulated by 100 nM and up to 10 μM of Ang II in the presence or absence of thapsigargin or 100 μM TRPC inhibitor 2-APB were measured in Fura-2AM loaded podocytes of the intact glomeruli. Depletion of internal Ca2+ stores with thapsigargin did not affect cell activation by Ang II, but 2-APB totally blocked calcium flux. This therefore allows hypothesizing that TRPC channels in the podocytes mediate calcium influx in response to Ang II. Western blotting and IHC staining revealed that TRPC1, 3 and 6 are expressed in the Sprague Dawley rat glomeruli. Single channel electrophysiological analysis with patch-clamp demonstrated that 100 nM Ang II acutely activates native TRPC-like channels in the podocytes, as well as TRPC6 channels transiently overexpressed in CHO cells together with the ATR1; the detected effect was mediated by changes in the channel open probability. The ability of podocytes to precisely regulate intracellular Ca2+ plays a central role in glomerular diseases, therefore, manipulating Ca2+ levels by inhibiting TRPC channels or their activators may be a useful strategy for treating patients with FSGS. In this study we provide evidence of Ang II-dependent activation of TRPC6 channels in podocytes, which might play a significant role in the development of kidney diseases.