TRPC6 up-regulation in Ang II-induced podocyte apoptosis might result from ERK activation and NF-kappaB translocation.
Angiotensin II (Ang II) has been recognized as an apoptosis inducer in podocytes, but the mechanism of apoptosis induced by Ang II is unclear. Transient receptor potential cation channel 6 (TRPC6) is a calcium channel located in podocyte membrane. The present study evaluated the alteration of TRPC6 expression and the Ca(2+) influx involved in Ang II-induced podocyte apoptosis. The possible pathways related to TRPC6 in Ang II-induced podocyte apoptosis were also investigated. The apoptosis of mouse podocytes (MPC5) was induced by Ang II. The protein level of TRPC6 was increased markedly in response to Ang II stimulation, and the intracellular Ca(2+) concentration was elevated. By transfection with TRPC6 siRNA, Ang II-induced podocyte apoptosis and the transient Ca(2+) influx were inhibited. Treated with extracellular signal-regulated kinase (ERK) pathway specific inhibitor U0126 or nuclear factor-kappaB (NF-kappaB) pathway specific inhibitor ammonium pyrrolidinedithiocarbamate (PDTC) and Ang II, respectively in podocytes, not only was the TRPC6 up-regulation reduced, but the podocyte apoptosis was also decreased. Moreover, the translocation of NF-kappaB in nucleus resulted from Ang II was reduced by treatment with U0126. In conclusion, the enhancement expression of TRPC6 as well as the increased Ca(2+) influx mediated by TRPC6 channels contributed to the podocyte apoptosis. The activation of ERK pathway and subsequent translocation of NF-kappaB was possibly necessary for the up-regulation TRPC6 induced by Ang II.
Zhang
Han
H
Department of Pediatrics, Peking University First Hospital, Beijing 100034, PR China.
Ding
Jie
J
Fan
Qingfeng
Q
Liu
Shufang
S
D000804:Angiotensin II / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis; D002070:Butadienes / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D004791:Enzyme Inhibitors / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051379:Mice; D052002:NF-kappa B p50 Subunit / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009570:Nitriles / Q000494:pharmacology; D050199:Podocytes / Q000502:physiology*; D011759:Pyrrolidines / Q000494:pharmacology; D050052:TRPC Cation Channels / Q000096:biosynthesis*; D000074287:TRPC6 Cation Channel; D013859:Thiocarbamates / Q000494:pharmacology; D015854:Up-Regulation
D002070:Butadienes; D004791:Enzyme Inhibitors; D052002:NF-kappa B p50 Subunit; D009570:Nitriles; D011759:Pyrrolidines; D050052:TRPC Cation Channels; D000074287:TRPC6 Cation Channel; D013859:Thiocarbamates; C492146:Trpc6 protein, mouse; C113580:U 0126; D000804:Angiotensin II; C073701:Nfkb1 protein, mouse; C020972:pyrrolidine dithiocarbamic acid; D048049:Extracellular Signal-Regulated MAP Kinases; D002118:Calcium