TRPC6-Mediated Ca2+ Signaling is Required for Hypoxia-Induced Autophagy in Human Podocytes

• Main Authors: Tianrong Ji, Chengwei Zhang, Linlin Ma, Qin Wang, Li Zou, Kexin Meng, Rui Zhang, Jundong Jiao
• Format: Article
• Language: English
• Published: Cell Physiol Biochem Press GmbH & Co KG 2018-08-01
• Series: Cellular Physiology and Biochemistry
• Subjects: Trpc6; Podocytes; Autophagy; Ca2+ signaling; Adenosine monophosphate-activated protein kinase
• Online Access: https://www.karger.com/Article/FullText/492351
• ISSN: 1015-8987; 1421-9778

Background/Aims: Intracellular Ca2+ signaling plays an important role in the regulation of autophagy. However, very little is known about the role of Ca2+ influx, which is induced by plasma membrane Ca2+ channels. Our previous study showed that transient receptor potential canonical channel-6 (TRPC6), a major Ca2+ influx pathway in podocytes, was activated by hypoxia. Here, we investigated whether TRPC6 is involved in hypoxia-induced autophagy in cultured human podocytes. Methods: In the present study, an immortalized human podocyte cell line was used. Fluo-3 fluorescence was utilized to determine intracellular Ca2+ concentration ([Ca2+]i), and western blotting was used to measure autophagy and protein expression. Results: We found that blockade TRPC6 by using either TRPC6 siRNA or a TRPC6 blocker attenuated hypoxia-induced autophagy, while enhancement of TRPC6 activity with a TRPC6 activator enhanced hypoxia-induced autophagy. Furthermore, TRPC6-dependent Ca2+ signaling is responsible for hypoxia-induced autophagy since both an intracellular and extracellular Ca2+ chelator abolished hypoxia-induced autophagy. Moreover, we found that blockade of TRPC6 by using either TRPC6 siRNA or a TRPC6 blocker decreased the expression of adenosine monophosphate-activated protein kinase (AMPK), an important signaling molecule in Ca2+-dependent autophagy activation, which is activated under hypoxic conditions. These data suggest that the involvement of TRPC6 in hypoxia-induced autophagy is associated with AMPK signaling. Conclusion: TRPC6 is essential for hypoxia-induced autophagy in podocytes.