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

Abstract

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 non-coding RNA (lncRNA), 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 NLRP3, while the overexpression of NLRP3 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.

Sanqi Oral Solution Mitigates Proteinuria in Rat Passive Heymann Nephritis and Blocks Podocyte Apoptosis via Nrf2/HO-1 Pathway

“…As highly specialized and terminal differentiated cells, podocyte have very limited ability of division and proliferation (Nagata, 2016). When injured by stimulating factors including C5b-9, podocytes are prone to death and eventually abscission occurs (Zhang et al, 2021). In the condition of podocyte death, apoptosis is an important form, and following the production of proteinuria and the progress of IMN.…”

Non-coding RNAs in necroptosis, pyroptosis and ferroptosis in cancer metastasis

“… Kcnq1ot1 miR-214-3p miR-486a-3p LncRNA Kcnq1ot1 induced pyroptosis in diabetic corneal endothelial kerotopathy [ 155 ]. Kcnq1ot1 induced pyroptosis was due to inhibiting miR-486a-3p and upregulating NLRP3 [ 156 ]. Knockdown Kcnq1ot1 inhibited gasdermin D cleavage to regulate pyroptosis [ 65 ].…”

MALAT1: A Pivotal lncRNA in the Phenotypic Switch of Gastric Smooth Muscle Cells via the Targeting of the miR-449a/DLL1 Axis in Diabetic Gastroparesis

“…Several studies have shown that lncRNAs play an important role in the pathogenesis of diabetes and its complications ( Zhang et al, 2020 ; He et al, 2020 ). We demonstrated that MALAT1 was elevated in the tissue samples from diabetic patients with DGP symptoms as well as in a murine model of DGP.…”