2. Academic Validation
  3. Renal tubular epithelial IGFBP7 interacts with PKM2 to drive renal lipid accumulation and fibrosis

Renal tubular epithelial IGFBP7 interacts with PKM2 to drive renal lipid accumulation and fibrosis

  • Mol Ther. 2025 Aug 6;33(8):3757-3777. doi: 10.1016/j.ymthe.2025.05.013.
Ju-Tao Yu 1,  Shuai-Shuai Xie 1,  Xiao-Yu Shen 1,  Zeng Li 1,  Xiao-Wei Hu 2,  Yao Zhang 1,  Ze-Hui Dong 1,  Jia-Nan Wang 1,  Xiang-Yu Li 1,  Yu-Hang Dong 1,  Chao Li 1,  Ming-Lu Ji 1,  Xiao-Guo Suo 1,  Chen Yang 3,  Juan Jin 4,  Wei Wang 5,  Jia-Gen Wen 1,  Ming-Ming Liu 1,  Li Li 6,  Qin Yang 7,  Xiao-Ming Meng 8
Affiliations

Affiliations

  • 1 Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, the Key Laboratory of Anti-inflammatory of Immune Medicines, Ministry of Education, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei 230032, China.
  • 2 Department of Clinical Pharmacy, Anhui Provincial Children's Hospital, Hefei 230051, China.
  • 3 Institute of Nephrology, Affiliated Hospital of Guangdong Medical University, 57 Renmin Road, Zhanjiang, Guangdong 524001, China.
  • 4 Department of Pharmacology, School of Basic Medical Sciences, Key Laboratory of Anti-inflammatory and Immunopharmacology, Ministry of Education, Anhui Medical University, Hefei 230032, China.
  • 5 Department of Urology, Institute of Urology, The First Affiliated Hospital of Anhui Medical University, Anhui Province Key Laboratory of Genitourinary Diseases, Anhui Medical University, Hefei 230032, China.
  • 6 National Key Laboratory for Prevention and Treatment of Multi-organ Injury, Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China. Electronic address: guilinlily3@i.smu.edu.cn.
  • 7 Department of Clinical Pharmacology, the Second Affiliated Hospital of Anhui Medical University, Hefei 230601, China. Electronic address: yqayefy@163.com.
  • 8 Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, the Key Laboratory of Anti-inflammatory of Immune Medicines, Ministry of Education, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei 230032, China. Electronic address: mengxiaoming@ahmu.edu.cn.
PMID: 40346800 DOI: 10.1016/j.ymthe.2025.05.013
Abstract

Renal fibrosis serves as a critical pathological mechanism driving the progression of chronic kidney disease (CKD). However, the pathogenesis and therapeutic targets involved in this process remain unclear. Interestingly, we currently found that IGFBP7 is highly expressed in tubular epithelial cells (TECs) from the fibrotic kidneys of human patients and animal models. However, their functional roles in abnormal kidney repair and renal fibrosis remain unclear. Here, we report that IGFBP7 knockout (KO) or TEC conditional KO (cKO) attenuated renal fibrosis in multiple mouse models, whereas IGFBP7 knock-in or restoration in IGFBP7-KO mice enhanced renal fibrosis. These in vivo findings were verified using cultured TECs and organoids generated from IGFBP7-cKO mice. Mechanistically, we found that IGFBP7 bound to Pyruvate Kinase M2 (PKM2) to promote the acetylation of PKM2 at the K433 site, thereby enhancing PKM2 dimerization and nuclear translocation, and subsequently accelerating lipid production and renal fibrosis via SREBP1-dependent mechanisms. Notably, through drug screening, we identified salmeterol (an asthma medication) as an IGFBP7 antagonist that effectively reduced fibrosis. Our findings reveal the IGFBP7/PKM2/SREBP1 axis as a central regulator of lipogenic fibrosis, offering genetic and pharmacological inhibition of IGFBP7 as promising therapeutic strategies for CKD.

Keywords

IGFBP7; PKM2; lipid disorders; renal fibrosis; salmeterol.

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