Background and Aims: There is accumulating evidence that sympathetic nervous hyperactivity contributes to the pathogenesis of glomerular sclerosis independent of blood pressure effects. A previous study showed that α₁-adrenoceptor (α₁-AR) antagonists inhibit mesangial cell (MC) proliferation. However, the underlying mechanism remains unclear. Methods and Results: We found that α₁-AR is expressed in a human mesangial cell line. The α₁-AR agonist phenylephrine (PE) induced Ca²⁺ influx as well as release from intracellular Ca²⁺ stores. Blockade of TRPC6 with siRNA, anti-TRPC6 antibodies and a TRPC blocker attenuated the PE-induced [Ca²⁺]_i increase. Additionally, the PE-induced [Ca²⁺]_i increase was phospholipase C dependent. Furthermore, PE induced a [Ca²⁺]_i increase even when the intracellular Ca²⁺ stores were already depleted. This effect was mimicked by an analog of diacylglycerol. These results suggested that, upon α₁-AR stimulation, TRPC6 mediates Ca²⁺ influx via a receptor-operated Ca²⁺ entry mechanism. Finally, TRPC6 contributes to the PE-induced MC proliferation. The mechanisms are associated with the extracellular signal-regulated kinase (ERK) signaling pathway because blockade of TRPC6 and chelation of extracellular Ca²⁺ abrogated PE-induced ERK1/2 abrogated PE-induced ERK1/2 phosphorylation. Conclusion: TRPC6 channels are involved in α₁-AR activation-induced Ca²⁺ entry, which mediates proliferation via ERK signaling in human MCs