Guo Shaowen, Wang Wenjun, Lv Gaopan, Ling Yun, Zhu Meifeng
Nanjing University of Traditional Chinese Medicine, Nanjing, China.
Changzhou Hospital of Chinese Medicine Affiliated to Nanjing University of Chinese Medicine, Nanjing University of Traditional Chinese Medicine, Changzhou, China.
PeerJ. 2025 Aug 27;13:e19940. doi: 10.7717/peerj.19940. eCollection 2025.
Kidney disease is a major global health issue, causing numerous deaths and a loss of life years. This prompts us to explore potential targets or mechanisms that may increase the likelihood of diagnosing and treating kidney diseases. N6-methyladenosine (mA) modifications dynamically regulate RNA through "writer" enzymes, "eraser" enzymes, and "reader" proteins, influencing its processing, stability, and translation efficiency. In cases of kidney disease, there is a likelihood that mA methylation is a significant contributor to the pathological mechanisms of acute kidney injury (AKI), chronic kidney disease (CKD), diabetic kidney disease (DKD), renal cell carcinoma (RCC), and lupus nephritis (LN). In this article, we explore the role and mechanisms of mA methylation in kidney diseases and its applications in the treatment of kidney diseases.
This review systematically evaluated the therapeutic relevance of mA methylation in renal diseases using a targeted search strategy across multiple databases (Scopus, PubMed, Web of Science, Google Scholar, bioRxiv, medRxiv) from January 1970 to May 2025. Study quality was assessed, and critical data elements were cataloged to ensure rigor.
The current research investigates mA methylation's role in kidney diseases, highlighting its significant impact on regulating gene expression, affecting cell signaling pathways, and modulating inflammation. In AKI, changes in mA modification levels are closely associated with the severity of kidney damage. Specifically, mA regulators such as METTL3 and FTO influence the progression of AKI by affecting gene expression, oxidative stress, and inflammation. Regarding CKD, decreased mA modification levels could potentially cause atypical gene expression in cells, thus impairing normal cellular functions. In diabetic nephropathy (DN), dysregulated expression of genes linked to mA methylation is closely associated with renal hypertrophy, proteinuria, and glomerulosclerosis. In LN, alterations in mA regulator expression are strongly linked to glomerular filtration rate (GFR).
Emerging studies link dysregulated mA machinery to diverse kidney diseases, including acute/chronic kidney injury (WTAP/METTL3/FTO in oxidative stress and fibrosis), and diabetic nephropathy (METTL14/FTO polymorphisms in susceptibility). Mechanistically, mA modulates TGF-β signaling, inflammatory responses, and gene networks underlying disease progression. Despite therapeutic promise, challenges persist in methodological standardization and understanding systemic regulatory roles. Future research should prioritize multi-omics integration, isoform-specific inhibitors, and longitudinal clinical validation. Interdisciplinary efforts to decode mA's multifaceted regulation may advance precision diagnostics and mechanism-based therapies, ultimately improving renal disease management.
肾脏疾病是一个重大的全球健康问题，导致众多死亡和生命年损失。这促使我们探索可能增加肾脏疾病诊断和治疗可能性的潜在靶点或机制。N6-甲基腺苷（m⁶A）修饰通过“书写器”酶、“擦除器”酶和“读取器”蛋白动态调节RNA，影响其加工、稳定性和翻译效率。在肾脏疾病中，m⁶A甲基化很可能是急性肾损伤（AKI）、慢性肾脏病（CKD）、糖尿病肾病（DKD）、肾细胞癌（RCC）和狼疮性肾炎（LN）病理机制的重要促成因素。在本文中，我们探讨了m⁶A甲基化在肾脏疾病中的作用和机制及其在肾脏疾病治疗中的应用。
本综述使用有针对性的检索策略，系统评估了1970年1月至2025年5月期间多个数据库（Scopus、PubMed、Web of Science、Google Scholar、bioRxiv、medRxiv）中m⁶A甲基化在肾脏疾病中的治疗相关性。评估了研究质量，并对关键数据元素进行了编目以确保严谨性。
当前研究调查了m⁶A甲基化在肾脏疾病中的作用，突出了其对调节基因表达、影响细胞信号通路和调节炎症的重大影响。在急性肾损伤中，m⁶A修饰水平的变化与肾脏损伤的严重程度密切相关。具体而言，METTL3和FTO等m⁶A调节剂通过影响基因表达、氧化应激和炎症来影响急性肾损伤的进展。对于慢性肾脏病，m⁶A修饰水平降低可能会导致细胞中出现非典型基因表达，从而损害正常细胞功能。在糖尿病肾病（DN）中，与m⁶A甲基化相关的基因表达失调与肾脏肥大、蛋白尿和肾小球硬化密切相关。在狼疮性肾炎中，m⁶A调节剂表达的改变与肾小球滤过率（GFR）密切相关。
新兴研究将失调的m⁶A机制与多种肾脏疾病联系起来，包括急性/慢性肾损伤（氧化应激和纤维化中的WTAP/METTL3/FTO）以及糖尿病肾病（易感性中的METTL14/FTO多态性）。从机制上讲，m⁶A调节转化生长因子-β信号、炎症反应以及疾病进展的基因网络。尽管具有治疗前景，但在方法标准化和理解系统调节作用方面仍存在挑战。未来的研究应优先进行多组学整合、异构体特异性抑制剂和纵向临床验证。跨学科努力解码m⁶A的多方面调节可能会推动精准诊断和基于机制的治疗，最终改善肾脏疾病管理。
