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

Shuqi Wei; Diwen Shou; Siyuan Huang; Yingsi Wang; Quanzhen Liu; Jinfa Liu; Xiaoyu Lv; Yuyi Zeng; Liting Wei; Han Lin; Jiechuan Chen; Yangxiao Chen; Haoyu Zhong; Yanqing Zhou; Wen Ma; Li Wang; Guojun Qian; Jing Guo; Donglin Sun

doi:10.1002/advs.202509351

journal article·2025-12Open access

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

Shuqi Wei, Diwen Shou, Siyuan Huang, Yingsi Wang, Quanzhen Liu, Jinfa Liu, Xiaoyu Lv, Yuyi Zeng, Liting Wei, Han Lin, Jiechuan Chen, Yangxiao Chen, Haoyu Zhong, Yanqing Zhou, Wen Ma, Li Wang, Guojun Qian, Jing Guo, Donglin Sun

Advanced Science· Volume 12· Issue 46

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Source abstract

Abstract

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.

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Research context

OpenAlex topics: Lipid metabolism and disorders · Liver Disease Diagnosis and Treatment · Pancreatitis Pathology and Treatment

SciVX discovery tags are terminology-based. OpenAlex topics are source-provided classifications.

Affiliations

Department of Urology Shenzhen Hospital Southern Medical University Shenzhen Guangdong 518100 China

The Third Affiliated Hospital of Sun Yat‐sen University Guangzhou 510630 China

Center for Cancer and Immunology Research State Key Laboratory of Respiratory Disease Affiliated Cancer Hospital of Guangzhou Medical University Guangzhou 510182 China

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

Department of Gastroenterology and Hepatology Guangzhou Digestive Disease Center Guangzhou First People's Hospital Guangzhou 510180 China

Department of Gastroenterology and Hepatology the Second Affiliated Hospital School of Medicine South China University of Technology Guangzhou 510180 China

Department of Gynecology and Obstetrics The First Affiliated Hospital of Guangzhou Medical University Guangzhou Guangdong 510120 China

Department of Gynecology and Obstetrics General Hospital of Southern Theater Command Guangzhou Guangdong 510010 China

Guangzhou Medical University Guangzhou Guangdong 510030 China

Department of Physiology and Pathophysiology School of Basic Medical Sciences Fudan University Shanghai 200032 China

College of Intelligent Medicine and Biotechnology Lingui Campus Guilin Medical University Guilin 541199 China

The Clinical Innovation & Research Center (CIRC) Shenzhen Hospital Southern Medical University Shenzhen Guangdong 518100 China

Clinical Laboratory Shenzhen Hospital Southern Medical University Shenzhen Guangdong 518100 China

Southern Medical University Affiliated Longhua People's Hospital Nephrology department Shenzhen Guangdong 518000 China

Key Laboratory of Anesthesiology Shanghai Jiao Tong University Ministry of Education Ren Ji Hospital Shanghai 200127 China

Center of oncology Heyou Hospital Shunde District Foshan City Guangdong 528000 China

Funding

National Natural Science Foundation of China

References (51)

Show source-provided references

1. 10.1016/j.kint.2023.10.01810.1016/j.kint.2023.10.018 ↗

2. 10.1146/annurev-physiol-022516-03422710.1146/annurev-physiol-022516-034227 ↗

3. 10.1038/s41392-022-01036-510.1038/s41392-022-01036-5 ↗

4. 10.1038/s41581-019-0248-y10.1038/s41581-019-0248-y ↗

5. 10.1053/j.ajkd.2021.11.01010.1053/j.ajkd.2021.11.010 ↗

6. 10.1038/s41574-024-00951-710.1038/s41574-024-00951-7 ↗

7. 10.1016/j.cmet.2024.04.01410.1016/j.cmet.2024.04.014 ↗

8. 10.3350/cmh.2022.044210.3350/cmh.2022.0442 ↗

9. 10.1016/j.phrs.2019.10461710.1016/j.phrs.2019.104617 ↗

10. 10.1038/s41581-021-00519-y10.1038/s41581-021-00519-y ↗

11. 10.1016/j.metabol.2020.15443310.1016/j.metabol.2020.154433 ↗

12. 10.1371/journal.pmed.100168010.1371/journal.pmed.1001680 ↗

13. 10.3748/wjg.v20.i42.1553910.3748/wjg.v20.i42.15539 ↗

14. 10.1136/gutjnl-2020-32308210.1136/gutjnl-2020-323082 ↗

15. 10.1016/j.diabet.2019.11.00310.1016/j.diabet.2019.11.003 ↗

16. 10.1111/liv.1399210.1111/liv.13992 ↗

17. 10.1016/j.metabol.2009.12.01210.1016/j.metabol.2009.12.012 ↗

18. 10.3390/ijms22211141610.3390/ijms222111416 ↗

19. 10.3390/ijms2302074710.3390/ijms23020747 ↗

20. 10.1016/j.jare.2022.08.00610.1016/j.jare.2022.08.006 ↗

21. 10.1016/j.plipres.2020.10106710.1016/j.plipres.2020.101067 ↗

22. 10.1038/srep2401310.1038/srep24013 ↗

23. 10.1038/s41467-023-40183-310.1038/s41467-023-40183-3 ↗

24. 10.1097/00005650-199504000-0001010.1097/00005650-199504000-00010 ↗

25. 10.1111/j.1523-1755.2005.00422.x10.1111/j.1523-1755.2005.00422.x ↗

26. 10.1146/annurev-physiol-022516-03421910.1146/annurev-physiol-022516-034219 ↗

27. 10.1126/sciadv.aaw507510.1126/sciadv.aaw5075 ↗

28. 10.1681/ASN.202006080610.1681/ASN.2020060806 ↗

29. 10.3945/an.113.00377210.3945/an.113.003772 ↗

30. 10.1038/nm.376210.1038/nm.3762 ↗

31. 10.1194/jlr.M00709610.1194/jlr.M007096 ↗

32. 10.1002/advs.20230629710.1002/advs.202306297 ↗

33. 10.1016/j.redox.2015.08.00610.1016/j.redox.2015.08.006 ↗

34. 10.1016/j.plipres.2021.10111010.1016/j.plipres.2021.101110 ↗

35. 10.1016/j.redox.2024.10309610.1016/j.redox.2024.103096 ↗

36. 10.1046/j.1523-1755.2001.060002614.x10.1046/j.1523-1755.2001.060002614.x ↗

37. 10.1093/intimm/dxw00610.1093/intimm/dxw006 ↗

38. 10.1038/s41392-023-01438-z10.1038/s41392-023-01438-z ↗

39. 10.3389/fimmu.2015.0021210.3389/fimmu.2015.00212 ↗

40. 10.1038/s41577-019-0127-610.1038/s41577-019-0127-6 ↗

41. 10.1016/j.matbio.2017.12.00210.1016/j.matbio.2017.12.002 ↗

42. 10.1038/s41419-023-06386-810.1038/s41419-023-06386-8 ↗

43. 10.1126/science.124207710.1126/science.1242077 ↗

44. 10.1210/clinem/dgab42510.1210/clinem/dgab425 ↗

45. 10.1016/j.jfma.2019.07.00710.1016/j.jfma.2019.07.007 ↗

46. 10.1016/j.bbrc.2012.07.03810.1016/j.bbrc.2012.07.038 ↗

47. 10.1038/cmi.2010.2210.1038/cmi.2010.22 ↗

48. 10.1146/annurev.immunol.021908.13271010.1146/annurev.immunol.021908.132710 ↗

49. 10.4049/jimmunol.090188110.4049/jimmunol.0901881 ↗

50. 10.1016/S0002-9440(10)63292-010.1016/S0002-9440(10)63292-0 ↗

51. 10.1146/annurev-immunol-052523-01514110.1146/annurev-immunol-052523-015141 ↗