Ramalingam Harini, Alvarez Jesus, Flaten Andrea, Cobo-Stark Patricia, Foster Nicholas, Grilli Elyse, Lakhia Ronak, Aboudehen Karam, Carroll Thomas, Patel Vishal
Department of Internal Medicine and Division of Nephrology, UT Southwestern Medical Center, Dallas, TX, 75390, USA.
Department of Medicine and Division of Nephrology, Stony Brook University, Stony Brook, NY, USA.
Nat Commun. 2025 May 28;16(1):4930. doi: 10.1038/s41467-025-60097-6.
The adult kidney lacks the ability to generate new nephrons, placing individuals born with low nephron counts at greater risk for chronic kidney disease as they age. Limited nutrient availability hinders nephron formation; however, the key metabolic dependencies remain unclear. Here we show that S-adenosylmethionine (SAM) and cellular transmethylation status are crucial determinants of the kidney's nephrogenic capacity. The RNA methyltransferase METTL3 serves as a SAM sensor and is essential for the fate determination of nephron progenitor cells (NPCs). Reducing transmethylation or inhibiting METTL3 blocks NPC differentiation and nephrogenesis, whereas enhancing transmethylation or increasing METTL3 activity facilitates an induced NPC population and increases nephron production. Additionally, we identify Lrpprc mRNA, encoding a mitochondrially enriched protein, as a key direct target of METTL3-mediated transmethylation. Accordingly, inhibiting LRPPRC negates the nephrogenic effects of SAM and METTL3. Our findings reveal a modifiable methionine-SAM-RNA transmethylation pathway that can be targeted to enhance nephron formation.
成年肾脏缺乏生成新肾单位的能力，这使得出生时肾单位数量较低的个体随着年龄增长患慢性肾病的风险更高。营养物质供应有限会阻碍肾单位形成；然而，关键的代谢依赖性仍不清楚。在此，我们表明S-腺苷甲硫氨酸（SAM）和细胞甲基化状态是肾脏肾生成能力的关键决定因素。RNA甲基转移酶METTL3作为SAM传感器，对肾单位祖细胞（NPC）的命运决定至关重要。降低甲基化或抑制METTL3会阻断NPC分化和肾生成，而增强甲基化或增加METTL3活性则有利于诱导NPC群体并增加肾单位生成。此外，我们确定编码线粒体富集蛋白的Lrpprc mRNA是METTL3介导的甲基化的关键直接靶点。因此，抑制LRPPRC可消除SAM和METTL3的肾生成作用。我们的研究结果揭示了一条可调节的甲硫氨酸-SAM-RNA甲基化途径，该途径可作为增强肾单位形成的靶点。
