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Kidney Week

Abstract: FR-PO063

Interferon Regulatory Factor 4 in Macrophages Promotes Renal Fibrosis Following Severe AKI

Session Information

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • Li, Zhilian, Vanderbilt University Medical Center, Nashville, Tennessee, United States
  • Overstreet, Jessica Marie, Vanderbilt University Medical Center, Nashville, Tennessee, United States
  • Chung, Sungjin, Vanderbilt University Medical Center, Nashville, United States
  • Wang, Yinqiu, Vanderbilt University Medical Center, Nashville, Tennessee, United States
  • Zhang, Ming-Zhi, Vanderbilt University Medical Center, Nashville, Tennessee, United States
  • Harris, Raymond C., Vanderbilt University Medical Center, Nashville, Tennessee, United States
Background

Acute kidney injury (AKI) is characterized by abrupt and reversible kidney dysfunction, and incomplete recovery from AKI leads to chronic kidney injury. Macrophage proliferation and polarization to an M2 phenotype plays a key role in recovery from AKI. However, M2 macrophages can produce profibrotic factors such as TGF-β and FIZZ1/RELMα, and their persistence may contribute to interstitial fibrosis when recovery from AKI is incomplete. Interferon regulatory factor 4 (IRF4) plays an important role in macrophage M2 polarization. The present study examined the potential role of macrophage IRF4 in recovery from AKI.

Methods


Wild type (WT, IRF4f/f) or macrophage IRF4-/- (LysM-Cre; IRF4f/f) mice (male, 3 months old, C57BL/6) were uninephrectomized, immediately followed by unilateral I/R with renal pedicle clamping for 32 min. Mice were sacrificed after 4 weeks.

Results



The effectiveness of macrophage IRF4 deletion was confirmed by qPCR in isolated renal macrophages. In cultured bone marrow monocytes, IRF4 deletion led to significant increases in LPS/IFN-γ-induced proinflammatory cytokines/chemokines. Macrophage IRF4-/- mice had delayed functional recovery during the first five days of recovery and more histologic injury at 5 days post I/R. At four weeks post-severe AKI, kidneys of IRF4-/- mice had marked decreases in M2 markers, IL-4Rα, CD206, FIZZ1/RELMα, CD209, and B7-H4 as well as decreases in proinflammatory cytokines/chemokines, IL-1α, IL-1β, IL-6, IL-23, CCL3, iNOS, TNF-α, and IFN-γ. Surprisingly, macrophage IRF4-/- mice had less severe kidney injury, as indicated by fewer protein casts and dilated tubules and less tubular atrophy. Sirius red and Masson’s Trichrome staining showed less renal interstitial fibrosis and decreased mRNA and protein levels of profibrotic and fibrotic components, TGF-β1, TGF-β2, CTGF, α-SMA, fibronectin, collagens I, III, IV as well as decreased immune cell infiltration in macrophage IRF4-/- mice.

Conclusion


Macrophage IRF4 facilitates functional and structural recovery of kidneys from AKI, possibly due to inhibiting proinflammatory cytokines/chemokines. When recovery from AKI is incomplete, IRF4-mediated pro-fibrotic, M2 polarization of macrophages/dendritic cells may contribute to development of fibrosis.

Funding

  • NIDDK Support