NLRP3 inflammasome mediates chronic intermittent hypoxia‐induced renal injury implication of the microRNA‐155/FOXO3a signaling pathway

Abstract

Chronic intermittent hypoxia (CIH), as the foremost pathophysiological change of obstructive sleep apnea (OSA), contributes to continued deterioration in renal function. Nucleotide-binding domain like receptor protein 3 (NLRP3) inflammasome is a multiprotein complex that triggers innate immune responses to infection and cell stress through activation of caspase-1 and maturation of inflammatory pro-interleukin-1β cytokine. Emerging evidence indicates that inhibition of the NLRP3 inflammasome ameliorates renal injury. Nevertheless, it is uncertain whether NLRP3 inflammasome participates in CIH-induced renal injury. The molecular mechanisms modulating NLRP3 inflammasome activation remain to be elucidated. Compared with wild-type mice, NLRP3 knockout mice dramatically protected them from kidney injury, as indicated by the restoration of creatinine levels, lessened histopathological alterations, and the suppression of macrophages infiltration stained with F4/80. NLRP3 deficiency notably reversed CIH-induced oxidative stress (malondialdehyde and superoxide dismutase), concomitantly with the abrogated apoptosis-related proteins and proinflammatory signaling pathway. Consistently, NLRP3-deficient tubular cells remarkably inhibited reactive oxygen species generation and NLRP3 inflammasome activation. Furthermore, our study revealed that microRNA-155 (miR-155) was augmented in the renal tissue and HK-2 cells exposed to CIH. In addition, we investigated the role of miR-155 in the regulation of NLRP3 inflammasome. Inhibition of miR-155 suppressed the CIH-induced NLRP3 inflammasome activation in renal tubular cells, whereas overexpression of miR-155 promoted oxidation and enhanced NLRP3 pathway. Collectively, we demonstrated that miR-155 might be a positive-regulator of NLRP3 pathway by inhibiting the targeted FOXO3a gene. These results established a link between the miR-155/FOXO3a pathway and the NLRP3 inflammasome, suggesting pharmacological blockage of NLRP3 as a potential therapeutic strategy for OSA-associated chronic kidney disease.

CircNr1h4 regulates the pathological process of renal injury in salt‐sensitive hypertensive mice by targeting miR‐155‐5p

“…42 Another study showed that miR-214 targets phosphatase and tensin homolog to F I G U R E 6 circRNA-miRNA-mRNA network in the kidneys of the control and DOCA-salt-induced hypertensive mice. 46 MiR-155 can also bind to the 3′UTR of Sirt1 to reduce its expression and decrease the expression of LC3-II and ATG5 in renal tubular injury of diabetic kidney disease. Validation of the differential expression of miRNAs (B) and mRNAs (C) in the kidneys between the control mice and the mice treated with DOCA-salt for 14 d using qPCR.…”

Melatonin Alleviates Radiation-Induced Lung Injury via Regulation of miR-30e/NLRP3 Axis

“…The cells were washed with PBS, permeabilized for 10 min with 0.1% Triton X-100 in PBS, washed with PBS, and incubated with primary antibodies of NLRP3 overnight at 4°C, as previously described [17]. After samples were washed with PBS, the secondary Alexa Fluor® 488-conjugated antibody (Santa Cruz) was added and incubated for 1 h at room temperature.…”

“…MicroRNAs (miRs) have been proven to act as key regulators of the cellular machinery and physiological processes, especially in the modulation of NLRP3 inflammasome [17]. Recently, it has been suggested that melatonin significantly enhanced the expression of microRNAs [18], which bind to specific complementary sequences in the 3′-untranslated regions (UTRs) of target mRNAs and control the posttranscriptional regulation [19].…”

Sleep Apnea and the Kidney

“…The molecular mechanisms involved in IH-induced renal injury are complex, with involvement of several pathways, such as the receptor for advanced glycation end-product (RAGE) [9] and its ligand, the high-mobility group box 1 protein (HMGB1) [5,9], toll-like receptor 4 (TLR-4) [10], oxidative stress [11•] and the NLRP3 inflammasome [12]. Blockade of such pathways resulted in decreased tubular damage, collagen deposition and apoptosis, lower release of inflammatory cytokines, and blunted albuminuria [9, 10, 11•, 12].…”