Renal fibrosis, a common feature of chronic kidney disease (CKD), is characterized by excessive deposition of extracellular matrix (ECM) leading to scar formation in the renal parenchyma. Active epithelial-mesenchymal communication (EMC), and the proliferation and activation of fibroblasts are implicated in the causation of renal fibrosis. Aurora-A kinase (AURKA) is a serine/threonine kinase required for the process of mitosis. Dysregulation of AURKA has been demonstrated in the context of various cancers. However, the role of AURKA in CKD-associated fibrosis has not been elucidated. MK-5108, a potent and highly selective AURKA inhibitor, was shown to exhibit anti-cancer activity in recent preclinical and clinical studies. In the present study, we investigated the role of MK-5108 in renal fibrosis employing animal and cell models. In vivo, AURKA was highly expressed in fibrotic kidneys of CKD patients and in mouse kidneys with unilateral ureteral obstruction (UUO). Post treatment with MK-5108 at the 3rd day after UUO remarkably alleviated renal fibrosis, possibly by inhibiting the proliferation and activation of fibroblasts and suppressing the phenotypic transition of renal cells. Moreover, the enhanced inflammatory factors in obstructive kidneys were also repressed. In vitro, MK-5108 treatment inhibited the pro-fibrotic response in renal cells induced by transforming growth factor-β1. Finally, overexpression of AURKA in renal fibroblasts promoted fibrotic response, while silencing AURKA showed anti-fibrotic effect, further confirming the pro-fibrotic role of AURKA. In this study, inhibition of AURKA by MK-5108 markedly attenuated renal fibrosis. MK-5108 is a potential therapeutic agent for treatment of renal fibrosis in CKD.

肾纤维化是慢性肾病 (CKD) 的一个共同特征，其特征是细胞外基质 (ECM) 过度沉积，导致肾实质瘢痕形成。活跃的上皮间质通讯 (EMC) 和成纤维细胞的增殖和活化与肾纤维化的原因有关。极光-A 激酶 (AURKA) 是有丝分裂过程所需的丝氨酸/苏氨酸激酶。AURKA 的失调已在各种癌症的背景下得到证实。然而，AURKA 在 CKD 相关纤维化中的作用尚未阐明。MK-5108 是一种有效且高度选择性的 AURKA 抑制剂，在最近的临床前和临床研究中显示出抗癌活性。在本研究中，我们使用动物和细胞模型研究了 MK-5108 在肾纤维化中的作用。体内，AURKA 在 CKD 患者的纤维化肾脏和单侧输尿管梗阻 (UUO) 的小鼠肾脏中高度表达。在 UUO 后第 3 天用 MK-5108 进行后处理显着减轻了肾纤维化，可能是通过抑制成纤维细胞的增殖和活化以及抑制肾细胞的表型转变。此外，阻塞性肾脏中增强的炎症因子也受到抑制。在体外，MK-5108 处理抑制了肾细胞中由转化生长因子-β1 诱导的促纤维化反应。最后，AURKA 在肾成纤维细胞中的过表达促进了纤维化反应，而沉默 AURKA 显示出抗纤维化作用，进一步证实了 AURKA 的促纤维化作用。在这项研究中，MK-5108 对 AURKA 的抑制显着减轻了肾纤维化。