2. Academic Validation
  3. Nonalcoholic Fatty Liver Disease Exacerbates the Advancement of Renal Fibrosis by Modulating Renal CCR2+PIRB+ Macrophages Through the ANGPTL8/PIRB/ALOX5AP Axis

Nonalcoholic Fatty Liver Disease Exacerbates the Advancement of Renal Fibrosis by Modulating Renal CCR2+PIRB+ Macrophages Through the ANGPTL8/PIRB/ALOX5AP Axis

  • Adv Sci (Weinh). 2025 Sep 25:e09351. doi: 10.1002/advs.202509351.
Shuqi Wei 1 2 3,  Diwen Shou 4 5 6,  Siyuan Huang 7 8,  Yingsi Wang 3,  Quanzhen Liu 9,  Jinfa Liu 4,  Xiaoyu Lv 10,  Yuyi Zeng 3,  Liting Wei 11,  Han Lin 9,  Jiechuan Chen 9,  Yangxiao Chen 3,  Haoyu Zhong 9,  Yanqing Zhou 12,  Wen Ma 13,  Li Wang 14,  Guojun Qian 15,  Jing Guo 16,  Donglin Sun 1
Affiliations

Affiliations

  • 1 Department of Urology, Shenzhen Hospital, Southern Medical University, Shenzhen, Guangdong, 518100, China.
  • 2 The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, China.
  • 3 Center for Cancer and Immunology Research, State Key Laboratory of Respiratory Disease, Affiliated Cancer Hospital of Guangzhou Medical University, Guangzhou, 510182, China.
  • 4 Department of Anesthesiology, Guangdong Provincial Key Laboratory of Major Obstetric Diseases, Guangdong Provincial Clinical Research Center for Obstetrics and Gynecology, The Third Affiliated Hospital, Guangzhou Medical University, Guangzhou, 510150, China.
  • 5 Department of Gastroenterology and Hepatology, Guangzhou Digestive Disease Center, Guangzhou First People's Hospital, Guangzhou, 510180, China.
  • 6 Department of Gastroenterology and Hepatology, the Second Affiliated Hospital, School of Medicine, South China University of Technology, Guangzhou, 510180, China.
  • 7 Department of Gynecology and Obstetrics, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, 510120, China.
  • 8 Department of Gynecology and Obstetrics, General Hospital of Southern Theater Command, Guangzhou, Guangdong, 510010, China.
  • 9 Guangzhou Medical University, Guangzhou, Guangdong, 510030, China.
  • 10 Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, China.
  • 11 College of Intelligent Medicine and Biotechnology, Lingui Campus, Guilin Medical University, Guilin, 541199, China.
  • 12 The Clinical Innovation & Research Center (CIRC), Shenzhen Hospital, Southern Medical University, Shenzhen, Guangdong, 518100, China.
  • 13 Clinical Laboratory, Shenzhen Hospital, Southern Medical University, Shenzhen, Guangdong, 518100, China.
  • 14 Southern Medical University Affiliated Longhua People's Hospital, Nephrology department, Shenzhen, Guangdong, 518000, China.
  • 15 Key Laboratory of Anesthesiology, Shanghai Jiao Tong University, Ministry of Education, Ren Ji Hospital, Shanghai, 200127, China.
  • 16 Center of oncology, Heyou Hospital, Shunde District, Foshan City, Guangdong, 528000, China.
PMID: 40995682 DOI: 10.1002/advs.202509351
Abstract

Renal fibrosis is a critical pathological hallmark of chronic kidney disease. Although nonalcoholic fatty liver disease (NAFLD) has been implicated in kidney disease progression, its specific role and underlying mechanisms in renal fibrosis remain poorly understood. This study aims to investigate these mechanisms by establishing a mouse model of renal fibrosis through unilateral ureteral obstruction (UUO) combined with a high-fat diet-induced NAFLD. Single-cell RNA Sequencing, untargeted metabolomics, flow cytometry, and immunofluorescence are performed, along with in vitro experiments involving primary renal macrophages and coculture models. It is demonstrated that NAFLD exacerbates renal fibrosis, as HFD-induced hepatocytes release significant levels of ANGPTL8, which activates renal CCR2+PIRB+ macrophages. These specialized macrophages disrupt linoleic acid metabolism and increase the production of inflammatory cytokines, aggravating renal fibrosis. In addition, CCR2+PIRB+ macrophages promote the activation and proliferation of Th17 cells, which can further contribute to the worsening of renal fibrosis. Thus, the ANGPTL8/PIRB/ALOX5AP axis is a crucial signaling pathway between the liver and kidneys, and CCR2+PIRB+ macrophages play a pivotal role in the progression of NAFLD-induced renal fibrosis. These findings suggest potential therapeutic targets to treat NAFLD-related renal fibrosis.

Keywords

ALOX5AP; ANGPTL8; macrophages; nonalcoholic fatty liver disease; renal fibrosis.

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