Li Jing, Chen Li-Ting, Wang You-Liang, Kang Mei-Xia, Liang Shi-Ting, Hong Xi-Zhen, Hou Fan Fan, Zhang Fu-Jian
Division of Nephrology, Nanfang Hospital, Southern Medical University; National Clinical Research Center for Kidney Disease; State Key Laboratory of Organ Failure Research; Guangdong Provincial Institute of Nephrology; Guangdong Provincial Key Laboratory of Renal Failure Research, Guangzhou, 510515, China.
Department of Critical Care Medicine, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, 450008, China.
Acta Pharmacol Sin. 2025 Apr;46(4):1002-1015. doi: 10.1038/s41401-024-01445-y. Epub 2025 Jan 7.
The ability of the mammalian kidney to repair or regenerate after acute kidney injury (AKI) is very limited. The maladaptive repair of AKI promotes progression to chronic kidney disease (CKD). Therefore, new strategies to promote the repair/regeneration of injured renal tubules after AKI are urgently needed. Hypoxia has been shown to induce heart regeneration in adult mice. However, it is unknown whether hypoxia can induce kidney regeneration after AKI. In this study, we used a prolyl hydroxylase domain inhibitor (PHDI), MK-8617, to mimic hypoxic conditions and found that MK-8617 significantly ameliorated ischemia reperfusion injury (IRI)-induced AKI. We also showed that MK-8617 dramatically facilitated renal tubule regeneration by promoting the proliferation of renal proximal tubular cells (RPTCs) after IRI-induced AKI. We then performed bulk mRNA sequencing and discovered that multiple nephrogenesis-related genes were significantly upregulated with MK-8617 pretreatment. We also showed that MK-8617 may alleviate proximal tubule injury by stabilizing the HIF-1α protein specifically in renal proximal tubular cells. Furthermore, we demonstrated that MK-8617 promotes the reprogramming of renal proximal tubular cells to Sox9 renal progenitor cells and the regeneration of renal proximal tubules. In summary, we report that the inhibition of prolyl hydroxylase improves renal proximal tubule regeneration after IRI-induced AKI by promoting the reprogramming of renal proximal tubular cells to Sox9 renal progenitor cells.
哺乳动物肾脏在急性肾损伤（AKI）后进行修复或再生的能力非常有限。AKI的适应性不良修复会促进慢性肾脏病（CKD）的进展。因此，迫切需要新的策略来促进AKI后受损肾小管的修复/再生。缺氧已被证明可诱导成年小鼠心脏再生。然而，尚不清楚缺氧是否能在AKI后诱导肾脏再生。在本研究中，我们使用脯氨酰羟化酶结构域抑制剂（PHDI）MK-8617模拟缺氧条件，发现MK-8617显著改善了缺血再灌注损伤（IRI）诱导的AKI。我们还表明，MK-8617通过促进IRI诱导的AKI后肾近端小管细胞（RPTCs）的增殖，极大地促进了肾小管再生。然后，我们进行了大量mRNA测序，发现多个与肾发生相关的基因在MK-8617预处理后显著上调。我们还表明，MK-8617可能通过特异性地稳定肾近端小管细胞中的HIF-1α蛋白来减轻近端小管损伤。此外，我们证明MK-8617促进肾近端小管细胞重编程为Sox9肾祖细胞以及肾近端小管的再生。总之，我们报告脯氨酰羟化酶的抑制通过促进肾近端小管细胞重编程为Sox9肾祖细胞来改善IRI诱导的AKI后的肾近端小管再生。
