Mechanism of circHIPK3-miRNA-124-3p/miRNA-148b-3p-Mediated Inflammatory Responses and Cell Senescence in <b><i>Candida albicans</i></b>-Induced Septic Acute Kidney Injury

Abstract

&lt;b&gt;&lt;i&gt;Introduction:&lt;/i&gt;&lt;/b&gt; Sepsis is a life-threatening inflammatory state that can result in septic acute kidney injury (SAKI). Circular RNAs (circRNAs) are implicated in various inflammatory diseases including SAKI. This study investigated the effect of circHIPK3 on inflammatory responses and cell senescence in &lt;i&gt;Candida albicans&lt;/i&gt;-induced SAKI. &lt;b&gt;&lt;i&gt;Methods:&lt;/i&gt;&lt;/b&gt; circHIPK3 expression and inflammatory factors in the serum of SAKI patients and healthy volunteers were detected. The murine and cell models of SAKI were established by &lt;i&gt;C. albicans&lt;/i&gt; and lipopolysaccharide induction, respectively. The effect of circHIPK3 on SAKI inflammatory responses and cell senescence was measured using ELISA, SA-β-gal staining, CCK-8, RT-qPCR, and Western blot. The binding relationships among circHIPK3, miR-124-3p, or miR-148b-3p and KLF6 or DNMT1/3a were confirmed. The binding of KLF6 and NLRP3 was determined, and the methylation level of the Klotho promoter was detected. Functional rescue experiments were performed to verify the effect of miR-124-3p or miR-148b-3p on SAKI. &lt;b&gt;&lt;i&gt;Results:&lt;/i&gt;&lt;/b&gt; circHIPK3 was highly expressed in SAKI. circHIPK3 silencing alleviated kidney injury in SAKI mice and enhanced SAKI cell viability by alleviating inflammatory responses and cell senescence. Mechanically, circHIPK3 upregulated KLF6 expression by competitively binding to miR-124-3p, thereby promoting the binding of KLF6 and NLRP3, activating NLRP3/caspase-1-mediated pyroptosis, and eventually aggravating SAKI inflammatory responses. circHIPK3 upregulated DNMT1/3a expression by competitively binding to miR-148b-3p, thus elevating the methylation level of Klotho promoter and accelerating SAKI cell senescence. Downregulation of miR-124-3p or miR-148b-3p attenuated the protective effect of circHIPK3 silencing on SAKI. &lt;b&gt;&lt;i&gt;Conclusion:&lt;/i&gt;&lt;/b&gt; circHIPK3 aggravated SAKI inflammatory responses via miR-124-3p/KLF6 and accelerated SAKI cell senescence via miR-148b-3p/DNMT1/3a.

The role of KDM4A‐mediated histone methylation on temozolomide resistance in glioma cells through the HUWE1/ROCK2 axis

“…Existing evidence strongly suggests that depleting ROCK2 can effectively counteract TMZ resistance in glioma cells by disrupting the DNA repair system, a conclusion consistent with our study's findings. 12 Our results strongly indicate that increasing ROCK2 expression significantly enhances the susceptibility of glioma cells to TMZ, as demonstrated by a notable increase in the IC50 value of T98G cells for TMZ. Additionally, the lack of HUWE1 within cells may contribute to platinum resistance, potentially by enhancing DNA damage repair mechanisms and promoting resistance to apoptosis.…”

“…11 In glioma, ROCK2 is over-activated in TMZ-resistant glioma cells, and its suppression enhances glioma cell sensitivity to TMZ. 12 Strategies aiming to downregulate ROCK2 expression, such as using nanocomposites, have shown potential in sensitizing glioma cells to TMZ. 13 However, the precise molecular mechanism underlying the inhibitory effect of ROCK2 on chemoresistance in glioma cells remains unclear.…”

“…Fasudil, a clinically utilized inhibitor of ROCKs, has demonstrated success in inhibiting the growth of chemotherapy‐resistant osteosarcoma cells 11 . In glioma, ROCK2 is over‐activated in TMZ‐resistant glioma cells, and its suppression enhances glioma cell sensitivity to TMZ 12 . Strategies aiming to downregulate ROCK2 expression, such as using nanocomposites, have shown potential in sensitizing glioma cells to TMZ 13 .…”

Cellular senescence: A potential mode of circular RNAs regulating prostate cancer

“…A fresh study recently showed that circXPO1 plays a key role in cigarette smoke‐induced inflammation and cellular senescence of alveolar epithelial cells in chronic obstructive pulmonary disease 94 . Moreover, circHIPK3 aggravated septic acute kidney injury (SAKI) inflammatory responses via miR‐124‐3p/KLF6 and accelerated SAKI cell senescence via miR‐148b‐3p/DNMT1/3a axis 95 …”

Circular RNAs in Acute Kidney Injury: Roles in Pathophysiology and Implications for Clinical Management

“…Similar findings were noted for circ-HIPK3 in a murine model of AKI induced by Candida albicans , where the downregulation of circ-HIPK3 ameliorated the inflammatory response to sepsis, with reduced levels of IL-6 and TNF-α but increased levels of IL-10. This was likely due to the interaction of circ-HIPK3 with miR-124-3p and miR-148b-3p [ 33 ].…”