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Silencing Long Non-coding RNA Kcnq1ot1 Limits Acute Kidney Injury by Promoting miR-204-5p and Blocking the Activation of NLRP3 Inflammasome.

ABSTRACT: Acute kidney injury (AKI) is a critical clinical disease characterized by an acute decrease in renal function. Long non-coding RNAs (LncRNAs) are important in AKI. This study aimed to explore the mechanism of lncRNA Kcnq1ot1 in AKI by sponging microRNA (miR)-204-5p as a competitive endogenous RNA (ceRNA). AKI mouse model and hypoxia/reoxygenation (H/R) model of human kidney (HK) cells were established. Kcnq1ot1 expression, cell proliferation, and apoptosis were measured. Binding relations among Kcnq1ot1, miR-204-5p, and NLRP3 were verified. Pathological changes and cell apoptosis were detected. The results showed that Kcnq1ot1 was highly expressed in the AKI model in vivo and in vitro. Kcnq1ot1 knockdown promoted cell proliferation and prevented apoptosis and inflammation. Furthermore, Kcnq1ot1 inhibited miR-204-5p expression by competitively binding to miR-204-5p in HK-2 cells. miR-204-5p targeted NLRP3 and NLRP3 overexpression averted the inhibiting effect of miR-204-5p on apoptosis and inflammation in HK-2 cells in vitro. Kcnq1ot1 knockdown in vivo promoted miR-204-5p expression, inhibited NLRP3 inflammasome activation, reduced levels of SCr, BUN, and KIM-1, and thus alleviated AKI and reduced apoptosis. In summary, silencing lncRNA Kcnq1ot1 inhibited AKI by promoting miR-204-5p and inhibiting NLRP3 inflammasome activation.

SUBMITTER: Wang J

PROVIDER: S-EPMC8632456 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Microtubules play critical roles in regulating the activation of NLRP3 inflammasome and microtubule-destabilizing agents such as colchicine have been shown to suppress the activation of this inflammasome. However, it remains largely unknown whether paclitaxel, a microtubule-stabilizing agent being used in cancer therapy, has any influences on NLRP3 inflammasome activation. Here we showed that paclitaxel pre-treatment greatly enhanced ATP- or nigericin-induced NLRP3 inflammasome activation as indicated by increased release of cleaved caspase-1 and mature IL-1?, enhanced formation of ASC speck, and increased gasdermin D cleavage and pyroptosis. Paclitaxel time- and dose-dependently induced ?-tubulin acetylation in LPS-primed murine and human macrophages and further increased ATP- or nigericin-induced ?-tubulin acetylation. Such increased ?-tubulin acetylation was significantly suppressed either by resveratrol or NAD+ (coenzyme required for deacetylase activity of SIRT2), or by genetic knockdown of MEC-17 (gene encoding ?-tubulin acetyltransferase 1). Concurrently, the paclitaxel-mediated enhancement of NLRP3 inflammasome activation was significantly suppressed by resveratrol, NAD+, or MEC-17 knockdown, indicating the involvement of paclitaxel-induced ?-tubulin acetylation in the augmentation of NLRP3 inflammasome activation. Similar to paclitaxel, epothilone B that is another microtubule-stabilizing agent also induced ?-tubulin acetylation and increased NLRP3 inflammasome activation in macrophages in response to ATP treatment. Consistent with the in vitro results, intraperitoneal administration of paclitaxel significantly increased serum IL-1? levels, reduced bacterial burden, dampened infiltration of inflammatory cells in the liver, and improved animal survival in a mouse model of bacterial infection. Collectively, our data indicate that paclitaxel potentiated NLRP3 inflammasome activation by inducing ?-tubulin acetylation and thereby conferred enhanced antibacterial innate responses, suggesting its potential application against pathogenic infections beyond its use as a chemotherapeutic agent.

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Silencing Long Non-coding RNA Kcnq1ot1 Limits Acute Kidney Injury by Promoting miR-204-5p and Blocking the Activation of NLRP3 Inflammasome.

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