Division of Nephrology, Nanfang Hospital, Southern Medical University; State Key Laboratory of Organ Failure Research; National Clinical Research Center for Kidney Disease; Guangdong Provincial Institute of Nephrology; Guangdong Provincial Key Laboratory of Renal Failure Research, Guangzhou, 510515, China.
Division of Nephrology, Department of Medicine, University of Connecticut School of Medicine, Farmington, CT, 06030, USA.
Int J Biol Sci. 2023 May 29;19(9):2860-2878. doi: 10.7150/ijbs.82417. eCollection 2023.
Acute kidney injury (AKI) is a refractory clinical syndrome with limited effective treatments. Amid AKI, activation of the extracellular signal-regulated kinase (ERK) cascade plays a critical role in promoting kidney repair and regeneration. However, a mature ERK agonist in treating kidney disease remains lacking. This study identified limonin, a member of the class of compounds known as furanolactones, as a natural ERK2 activator. Employing a multidisciplinary approach, we systemically dissected how limonin mitigates AKI. Compared to vehicles, pretreatment of limonin significantly preserved kidney functions after ischemic AKI. We revealed that ERK2 is a significant protein linked to the limonin's active binding sites through structural analysis. The molecular docking study showed a high binding affinity between limonin and ERK2, which was confirmed by the cellular thermal shift assay and microscale thermophoresis. Mechanistically, we further validated that limonin promoted tubular cell proliferation and reduced cell apoptosis after AKI by activating ERK signaling pathway . and , blockade of ERK abolished limonin's capacity of preventing tubular cell death under hypoxia stress. Our results indicated that limonin is a novel ERK2 activator with strong translational potential in preventing or mitigating AKI.
急性肾损伤 (AKI) 是一种难治性临床综合征，有效治疗方法有限。在 AKI 中，细胞外信号调节激酶 (ERK) 级联的激活在促进肾脏修复和再生中起着关键作用。然而，用于治疗肾脏疾病的成熟 ERK 激动剂仍然缺乏。本研究发现，柠檬苦素是呋喃内酯类化合物中的一种，是一种天然的 ERK2 激活剂。通过采用多学科方法，我们系统地剖析了柠檬苦素如何减轻 AKI。与载体相比，柠檬苦素预处理可显著保护缺血性 AKI 后的肾脏功能。我们通过结构分析发现 ERK2 是与柠檬苦素的活性结合位点相关的重要蛋白质。分子对接研究表明柠檬苦素与 ERK2 之间具有很高的结合亲和力，细胞热转移测定和微量热泳法进一步证实了这一点。从机制上讲，我们进一步验证了柠檬苦素通过激活 ERK 信号通路促进肾小管细胞增殖和减少细胞凋亡，从而减轻 AKI。并且，ERK 的阻断消除了柠檬苦素在缺氧应激下防止肾小管细胞死亡的能力。我们的研究结果表明，柠檬苦素是一种新型的 ERK2 激活剂，在预防或减轻 AKI 方面具有很强的转化潜力。
