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Kidney Week

Abstract: FR-PO068

Senescence Associated Secretory Phenotype: Role of Plasminogen Activator Inhibitor-2 (PAI-2) in Acute and Chronic Kidney Disease

Session Information

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • Sen, Payel, Hannover Medical School, Hannover, Germany
  • Helmke, Alexandra, Hannover Medical School, Hannover, Germany
  • Von Vietinghoff, Sibylle, Hannover Medical School, Hannover, Germany
  • Rong, Song, Hannover Medical School, Hannover, Germany
  • Braesen, Jan H., Hannover Medical School, Hannover, Germany
  • Haller, Hermann G., Hannover Medical School, Hannover, Germany
  • Melk, Anette, Hannover Medical School, Hannover, Germany
  • Schmitt, Roland, Hannover Medical School, Hannover, Germany
Background

One of the important mechanisms that play a role in age-related kidney disease is cellular senescence and the senescence associated secretory phenotype (SASP), which activates fibroblasts and causes immune cell infiltration. We identified plasminogen activator inhibitor-2 (PAI-2) as an upregulated secreted protein in senescent primary tubular epithelial cells (PTEC). PAI-2 is best known for its expression by macrophages, which are integral in post-injury kidney repair. Therefore, we intended to study the role of PAI-2 in the renal tubular SASP and immune surveillance in AKI and CKD.

Methods

Microarray was used for SASP analysis in PTEC. PAI-2 mRNA expression was tested in PTECs after treatment with Phorbol and γ-irradiation. HEK cells transduced with PAI-2 were co-cultured with fibroblasts. PTEC and bone marrow derived macrophages (BMDM) were extracted from wild type (WT) and PAI-2 knock out (KO) mice. To assess differences in post-injury repair, PAI-2 WT and KO mice were subjected to ischemia/reperfusion (I/R) and unilateral ureteral obstruction (UUO).

Results

PTEC derived from PAI-2 KO mice showed higher proliferation and lower expression of senescence marker p16INK4a after Phorbol treatment. In co-culture assays secreted PAI-2 activated fibroblasts. BMDMs extracted from WT mice had a stronger inflammatory phenotype after activation with LPS and IFNγ. While in acute phase post I/R PAI-2 KO kidneys had a reduced damage load, PAI-2 KO was associated with enhanced chronic damage during the later phase of I/R. In UUO, the KO kidney had more damage in acute as well as chronic phase. WT kidneys compared to KO showed steady decline in classically as well as alternatively activated macrophages in the later time points in both forms of injury.

Conclusion

PAI-2 is produced and secreted by tubular cells upon stress and during senescence. In the peritubular milieu, PAI-2 plays a heterogeneous role by promoting senescence and activating fibroblasts. It also strongly affects macrophage polarization and infiltration. While PAI-2 might have damaging effects during early renal injury our results indicate that PAI-2 is needed for long-term adaptation. In summary, PAI-2 is a novel renal SASP component which has an important impact on kidney adaptive repair.