title: Calcium entry via TRPC6 mediates albumin overload-induced endoplasmic reticulum stress and apoptosis in podocytes.
abstract: Albumin, which is the most abundant component of urine proteins, exerts injurious effects on renal cells in chronic kidney diseases. However, the toxicity of albumin to podocytes is not well elucidated. Here, we show that a high concentration of albumin triggers intracellular calcium ([Ca(2+)](i)) increase through mechanisms involving the intracellular calcium store release and extracellular calcium influx in conditionally immortalized podocytes. The canonical transient receptor potential-6 (TRPC6) channel, which is associated with a subset of familial forms of focal segmental glomerulosclerosis (FSGS) and several acquired proteinuric kidney diseases, was shown to be one of the important Ca(2+) permeable ion channels in podocytes. Therefore we explored the role of TRPC6 on albumin-induced functional and structural changes in podocytes. It was found that albumin-induced increase in [Ca(2+)](i) was blocked by TRPC6 siRNA or SKF-96365, a blocker of TRP cation channels. Long-term albumin exposure caused an up-regulation of TRPC6 expression in podocytes, which was inhibited by TRPC6 siRNA. Additionally, the inhibition of TRPC6 prevented the F-actin cytoskeleton disruption that is induced by albumin overload. Moreover, albumin overload induced expression of the endoplasmic reticulum (ER) stress protein GRP78, led to caspase-12 activation and ultimately podocyte apoptosis, all of which were abolished by the knockdown of TRPC6 using TRPC6 siRNA. These results support the view that albumin overload may induce ER stress and the subsequent apoptosis in podocytes via TRPC6-mediated Ca(2+) entry.
authors.affiliation: Department of Nephrology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Shan
authors.initials: S
authors.lastname: Chen
authors.forename: Fang-Fang
authors.initials: FF
authors.lastname: He
authors.forename: Hui
authors.initials: H
authors.lastname: Wang
authors.forename: Zhan
authors.initials: Z
authors.lastname: Fang
authors.forename: Ning
authors.initials: N
authors.lastname: Shao
authors.forename: Xiu-Juan
authors.initials: XJ
authors.lastname: Tian
authors.forename: Jian-She
authors.initials: JS
authors.lastname: Liu
authors.forename: Zhong-Hua
authors.initials: ZH
authors.lastname: Zhu
authors.forename: Yu-Mei
authors.initials: YM
authors.lastname: Wang
authors.forename: Sheng
authors.initials: S
authors.lastname: Wang
authors.forename: Kai
authors.initials: K
authors.lastname: Huang
authors.forename: Chun
authors.initials: C
authors.lastname: Zhang
mesh_terms: D008841:Actin Cytoskeleton / Q000187:drug effects / Q000378:metabolism; D000418:Albumins / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling; D053454:Caspase 12 / Q000378:metabolism; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress; D005434:Flow Cytometry; D051379:Mice; D008856:Microscopy, Fluorescence; D050199:Podocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D034741:RNA, Small Interfering; D050052:TRPC Cation Channels / Q000378:metabolism / Q000502:physiology*; D000074287:TRPC6 Cation Channel; D014162:Transfection
chemical_list: D000418:Albumins; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717248:Hspa5 protein, mouse; D034741:RNA, Small Interfering; D050052:TRPC Cation Channels; D000074287:TRPC6 Cation Channel; C492146:Trpc6 protein, mouse; D053454:Caspase 12; D002118:Calcium