Long noncoding RNA Kcnq1ot1 promotes sC5b-9-induced podocyte pyroptosis by inhibiting miR-486a-3p and upregulating NLRP3

• Published in: American Journal of Physiology: Cell Physiology Vol. 320; no. 3; p. C355
• Main Authors: Zhang, Chunjian, Gong, Yimeng, Li, Na, Liu, Xiaoyan, Zhang, Yunzhu, Ye, Fangze, Guo, Qiang, Zheng, Jiaxin
• Format: Journal Article
• Language: English
• Published: United States 01-03-2021
• Subjects: Animals; Cells, Cultured; Complement Membrane Attack Complex - pharmacology; Mice; MicroRNAs - genetics; NLR Family, Pyrin Domain-Containing 3 Protein - genetics; Podocytes - drug effects; Potassium Channels, Voltage-Gated - genetics; Pyroptosis - drug effects; Pyroptosis - genetics; RNA, Long Noncoding - genetics; Transcription, Genetic - drug effects; Transcription, Genetic - genetics; Up-Regulation - drug effects; Up-Regulation - genetics; Kcnq1ot1; sublytic complement; NLRP3 inflammasome; podocyte injury; miR-486a-3p
• ISSN: 1522-1563
• DOI: 10.1152/ajpcell.00403.2020

Podocytes are epithelial cells adhering glomerular capillaries, which regulate the integrity of glomerular filtration barrier. Irreversible podocyte injury induces glomerular inflammation and causes chronic renal diseases. Kcnq1ot1, a long noncoding RNA, participates in the pathogenesis of diabetic retinopathy and cardiomyopathy. However, its function in podocyte injury is elusive. Pyroptosis of murine podocyte MPC5 was triggered by sublytic complement C5b-9 (sC5b-9) for subsequent in vitro functional and mechanistic investigation. Gain/loss-of-function analysis was conducted to examine the functional role of Kcnq1ot1 in podocyte pyroptosis. Meanwhile, the molecular mechanism of Kcnq1ot1's effect on podocyte injury was explored by identifying downstream molecules and their intermediate interactions. Kcnq1ot1 was upregulated in sC5b-9-induced podocytes, and silencing Kcnq1ot1 could inhibit sC5b-9's effect on podocyte pyroptosis. We also identified the interaction between Kcnq1ot1 and miR-486a-3p, through which Kcnq1ot1 mediated miR-486a-3p inhibition by sC5b-9. Furthermore, miR-486a-3p reduced the transcriptional activity of
, while the overexpression of
enhanced sC5b-9's effect on podocyte pyroptosis through activating NLRP3 inflammasome. sC5b-9 induces pyroptosis in podocytes through modulating the Kcnq1ot1/miR-486a-3p/NLRP3 regulatory axis, and these uncovered key molecules might facilitate podocyte-targeted treatment for renal inflammatory diseases.