Rossi M N, Ciolfi A, Matteo V, Pedace L, Nardini C, Loricchio E, Caiello I, Bellomo F, Taranta A, De Leo E, Tartaglia M, Emma F, De Benedetti F, Miele E, Prencipe G
Laboratory of Rheumatology, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
Department of Science, University of Roma Tre, Rome, Italy.
Front Cell Dev Biol. 2025 Aug 21;13:1638123. doi: 10.3389/fcell.2025.1638123. eCollection 2025.
Nephropathic cystinosis is a rare genetic disorder characterized by cystine accumulation in lysosomes that causes early renal dysfunction and progressive chronic kidney disease. Although several metabolic pathways, including oxidative stress and inflammation, have been implicated in the progression of renal parenchyma damage, the precise mechanisms driving its progression are not fully understood. Recent studies suggest that epigenetic modifications, particularly DNA methylation (DNAm), play a critical role in the development of chronic kidney disease. We hypothesized that epigenetic dysregulation may contribute to the progression of kidney disease in cystinosis.
To investigate this, we conducted genome-wide DNAm analyses on kidneys harvested from 6-month-old wild type (WT) and mice, a well-established model of cystinosis.
Our analysis revealed extensive DNAm alterations in cystinotic kidneys, characterized by a significant hypermethylation profile. Interestingly, the majority of differentially methylated CpG sites were located within gene bodies and to a lesser extent in promoter and enhancer regions. Methylation changes were primarily found in genes and pathways crucial for kidney function, particularly those related to the physiology of the proximal tubules. Importantly, DNAm changes correlated with changes in gene expression, as validated by qPCR analyses of key genes. Furthermore, treatment of human proximal tubular epithelial cells with the demethylating agent decitabine resulted in the upregulation of critical transporter genes, suggesting a potential therapeutic approach.
These findings underscore the role of epigenetic regulation in the progression of kidney damage in cystinosis and suggest that DNAm could serve as a promising target for novel therapeutic strategies.
肾病型胱氨酸贮积症是一种罕见的遗传性疾病，其特征是溶酶体中胱氨酸蓄积，导致早期肾功能障碍和进行性慢性肾病。尽管包括氧化应激和炎症在内的几种代谢途径与肾实质损伤的进展有关，但其进展的确切机制尚未完全明确。最近的研究表明，表观遗传修饰，尤其是DNA甲基化（DNAm），在慢性肾病的发展中起关键作用。我们推测表观遗传失调可能促进胱氨酸贮积症患者肾病的进展。
为了研究这一点，我们对从6个月大的野生型（WT）小鼠和胱氨酸贮积症成熟模型小鼠获取的肾脏进行了全基因组DNAm分析。
我们的分析揭示了胱氨酸贮积症小鼠肾脏中广泛的DNAm改变，其特征是显著的高甲基化谱。有趣的是，大多数差异甲基化的CpG位点位于基因体内，在启动子和增强子区域的程度较小。甲基化变化主要发生在对肾功能至关重要的基因和途径中，特别是那些与近端小管生理学相关的基因和途径。重要的是，DNAm变化与基因表达变化相关，这通过关键基因的qPCR分析得到验证。此外，用去甲基化剂地西他滨处理人近端肾小管上皮细胞导致关键转运蛋白基因上调,这提示了一种潜在的治疗方法。
这些发现强调了表观遗传调控在胱氨酸贮积症肾损伤进展中的作用，并表明DNAm可能成为新治疗策略的一个有前景的靶点。
