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Objectives <p>Clarify the role of progranulin (PGRN) in renal fibrosis and its regulatory mechanism on macrophage efferocytosis.</p> Methods <p>To investigate the effect of PGRN on renal fibrosis, construct PGRN-deficient (PGRN<sup>−/−</sup>) mice and establish a renal fibrosis model induced by unilateral ureteral obstruction (UUO). The degree of kidney injury and fibrosis was evaluated through histological examination, immunohistochemical detection, enzyme-linked immunosorbent assay, and TUNEL assay. To evaluate the effect of PGRN on the efferocytosis ability, BMDMs extracted from PGRN<sup>−/−</sup> mice were co-cultured with apoptotic HK-2 cells. Efferocytosis activity was evaluated by flow cytometry and immunofluorescence. To analyze the molecular mechanism, conduct a transcriptomics analysis. The protein binding relationship was verified through co-immunoprecipitation and molecular docking. The changes in PGRN after interfering with signaling pathways were detected by qRT-PCR and Western blotting.</p> Results <p>The deficiency of PGRN significantly alleviated the renal tubular damage and tubular apoptosis induced by UUO. Additionally, it was observed that the infiltration of Mertk<sup>^+</sup>CD68<sup>^+</sup> macrophages increased, indicating that PGRN knockout enhanced phagocytosis. In vitro experiments showed that PGRN knockout BMDMs had enhanced phagocytosis of apoptotic HK2. Sequencing results revealed significant differences in the JAK-STAT pathway. Further studies found that the functional effect of this pathway was mainly mediated by STAT1/2, and overexpression of STAT1/2 reversed the enhanced phagocytosis induced by PGRN deficiency, rather than JAK. Mechanistically, PGRN directly binds to PPAR-δ, and its absence upregulates PPAR-δ, inhibiting the downstream expression of STAT1/2, thereby enhancing phagocytosis. However, knocking down or mutating PPAR-δ eliminates this effect.</p> Conclusion <p>PGRN inhibits macrophage efferocytosis during renal fibrosis by binding and inhibiting PPAR-δ, thereby activating the STAT1/2 signaling pathway and impairing the clearance of apoptotic cells.</p>

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Progranulin impairs efferocytosis of macrophages in renal fibrosis by negatively regulating PPAR-δ-mediated inhibition of the JAK-STAT signaling pathway

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年2月7日

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  • Yang Zhao,
  • Weichao Tu,
  • Yang Liu,
  • Xiaoqian Yang,
  • Yueyan Li,
  • Hao Yan

摘要

Objectives

Clarify the role of progranulin (PGRN) in renal fibrosis and its regulatory mechanism on macrophage efferocytosis.

Methods

To investigate the effect of PGRN on renal fibrosis, construct PGRN-deficient (PGRN−/−) mice and establish a renal fibrosis model induced by unilateral ureteral obstruction (UUO). The degree of kidney injury and fibrosis was evaluated through histological examination, immunohistochemical detection, enzyme-linked immunosorbent assay, and TUNEL assay. To evaluate the effect of PGRN on the efferocytosis ability, BMDMs extracted from PGRN−/− mice were co-cultured with apoptotic HK-2 cells. Efferocytosis activity was evaluated by flow cytometry and immunofluorescence. To analyze the molecular mechanism, conduct a transcriptomics analysis. The protein binding relationship was verified through co-immunoprecipitation and molecular docking. The changes in PGRN after interfering with signaling pathways were detected by qRT-PCR and Western blotting.

Results

The deficiency of PGRN significantly alleviated the renal tubular damage and tubular apoptosis induced by UUO. Additionally, it was observed that the infiltration of Mertk^+CD68^+ macrophages increased, indicating that PGRN knockout enhanced phagocytosis. In vitro experiments showed that PGRN knockout BMDMs had enhanced phagocytosis of apoptotic HK2. Sequencing results revealed significant differences in the JAK-STAT pathway. Further studies found that the functional effect of this pathway was mainly mediated by STAT1/2, and overexpression of STAT1/2 reversed the enhanced phagocytosis induced by PGRN deficiency, rather than JAK. Mechanistically, PGRN directly binds to PPAR-δ, and its absence upregulates PPAR-δ, inhibiting the downstream expression of STAT1/2, thereby enhancing phagocytosis. However, knocking down or mutating PPAR-δ eliminates this effect.

Conclusion

PGRN inhibits macrophage efferocytosis during renal fibrosis by binding and inhibiting PPAR-δ, thereby activating the STAT1/2 signaling pathway and impairing the clearance of apoptotic cells.