Kidney aging accelerates the progression of various acute and chronic kidney diseases and can also induce pathological changes in other organs throughout the body. Circular RNAs (circRNAs), have been demonstrated to play a vital role in aging and age-related diseases. However, biological functions and the underlying molecular mechanism of circRNAs in kidney aging remain largely unclear. Uncovering the functions of circRNAs in kidney aging and their underlying regulatory mechanisms may shed new light on the development of novel diagnostic and therapeutic strategies for human aging. Here we report the important role of circVmn2r1 in the progression of kidney aging. We found that circVmn2r1 was one of the top expressed circRNAs in mouse kidney by RNA sequencing and was significantly upregulated in 24-month-old mouse kidney compared to 3-month-old. More importantly, we demonstrated that overexpression of circVmn2r1 promoted kidney aging in senescence-accelerated mouse prone 8 (SAMP8) mice. Cellular assays with mouse kidney tubular epithelium (TCMK-1) cells under both gain-of-function and loss-of-function conditions demonstrated that circVmn2r1 inhibited proliferation and promoted senescence, whereas miR-223-3p counteracted these effects. Mechanistic analysis demonstrated that circVmn2r1 acted as a miR-223-3p sponge to relieve the repressive effect of miR-223-3p on its target NLRP3, which we proved could inhibit proliferation and promote senescence of TCMK-1 cells. Our results indicate that circVmn2r1 promotes kidney aging through acting as a miR-223-3p sponge, consequently upregulating NLRP3 expression, and can be a valuable diagnostic marker and an important therapeutic target for kidney aging.

中文翻译：

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环状RNA circVmn2r1作为miR-223-3p海绵通过调节小鼠NLRP3表达促进肾脏衰老

肾脏衰老会加速各种急慢性肾脏疾病的进展，还会诱发全身其他器官的病理变化。环状RNA（circRNA）已被证明在衰老和与年龄相关的疾病中发挥着至关重要的作用。然而，circRNA 在肾脏衰老中的生物学功能和潜在分子机制仍不清楚。揭示 circRNA 在肾脏衰老中的功能及其潜在的调节机制可能为人类衰老的新型诊断和治疗策略的开发提供新的思路。在这里，我们报告了 circVmn2r1 在肾脏衰老进程中的重要作用。通过 RNA 测序，我们发现 circVmn2r1 是小鼠肾脏中表达量最高的 circRNA 之一，并且与 3 个月大的小鼠肾脏相比，24 个月大的小鼠肾脏中的表达显着上调。更重要的是，我们证明了 circVmn2r1 的过度表达会促进衰老加速的 mouse pron 8 (SAMP8) 小鼠的肾脏衰老。在功能获得和功能丧失条件下对小鼠肾小管上皮 (TCMK-1) 细胞进行的细胞测定表明，circVmn2r1 抑制增殖并促进衰老，而 miR-223-3p 抵消这些作用。机制分析表明，circVmn2r1作为miR-223-3p海绵，缓解miR-223-3p对其靶标NLRP3的抑制作用，从而抑制TCMK-1细胞的增殖并促进衰老。我们的结果表明，circVmn2r1 通过充当 miR-223-3p 海绵来促进肾脏衰老，从而上调 NLRP3 表达，并且可以成为肾脏衰老的有价值的诊断标记物和重要的治疗靶点。