Inhibition of HIF-prolyl hydroxylase promotes renal tubule regeneration via the reprogramming of renal proximal tubular cells  

作　　者：Jing Li Li-ting Chen You-liang Wang Mei-xia Kang Shi-ting Liang Xi-zhen Hong Fan Fan Hou Fu-jian Zhang 

机构地区：[1]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 [2]Department of Critical Care Medicine,The Affiliated Cancer Hospital of Zhengzhou University&Henan Cancer Hospital,Zhengzhou,450008,China

出　　处：《Acta Pharmacologica Sinica》2025年第4期1002-1015,共14页中国药理学报(英文版)

基　　金：supported by the National Natural Science Foundation of China(82470812 to FJZ);Guangdong Basic and Applied Basic Research Foundation(2024A1515012857 to FJZ);the National Natural Science Foundation of China(Key Program)(82030022 to FFH);the Program of Introducing Talents of Discipline to Universities,111 Plan(D18005 to FFH);the Key Technologies R&D Program of Guangdong Province(2023B1111030004 to FFH);the Guangdong Provincial Clinical Research Center for Kidney Disease(2020B1111170013 to FFH).

摘　　要：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-1αprotein 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.

关 键 词：HYPOXIA prolyl hydroxylase domain inhibitor HIF-1α renal proximal tubular cells chemical reprogramming Sox9+renal progenitor cells renal regeneration 

分 类 号：R692[医药卫生—泌尿科学]