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Kidney Week

Abstract: FR-PO089

Impact of Aging on Transition of AKI to CKD

Session Information

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • Kim, Myung-Gyu, Korea University Anam Hospital, Seoul, Seoul, Korea (the Republic of)
  • Yang, Jihyun, Korea University Anam Hospital, Seoul, Seoul, Korea (the Republic of)
  • Oh, Sewon, Korea University Anam Hospital, Seoul, Seoul, Korea (the Republic of)
  • Jo, Sang-Kyung, Korea University Anam Hospital, Seoul, Seoul, Korea (the Republic of)
Background

Although acute kidney injury (AKI) in the elderly is thought to contribute to a higher incidence of end-stage renal disease, mechanisms underlying the transition from AKI to chronic kidney disease (CKD) in elderly is poorly understood. Here, we investigated the effects of aging on AKI to CKD transition in animal model of ischemia-reperfusion injury (IRI).

Methods

Aged (48wks) and young (8wks) C57BL/6 mice were subjected to bilateral IRI. Cytokine level as well as functional, histological changes were examined on days 1, 3, 7, and 28 days.

Results

Baseline level of proinflammatory cytokines were slightly but significantly elevated in the kidneys of aged mice than in young mice, suggesting the presence inflammaging. Compared to young mice, kidneys from aged mice showed a persistent M1 dominant inflammation with increased iNOS, TNF-a and IFN-r expression during the recovery phase. Among several factors for macrophage M2 polarization, increase of colony stimulating factor-1 (CSF-1) and interferon regulatory factor-4 (IRF-4) were significantly blunted in aged mice. However, the in vitro macrophage polarization into M2a or M2c by IL-4/IL-13 or IL-10/TGF-b stimulation was not different between young and aged bone marrow derived mononuclear cell, suggesting that macrophage interaction with adjacent cells might be responsible for persistent M1 mediated inflammation in aged mice. Immunohistochemistry and western blot analysis showed that tissue inhibitor of metalloproteinase-2 (TIMP2) expression significantly increased in tubules of aged mice, suggesting that increase of tubule cells that are in the state of cell cycle arrest. In vitro transwell experiment showed that bone marrow derived mononuclear cells cocultured with mouse tubular cells pretreated with inducer of cell cycle arrest showed significantly impaired M2 polarization compared with those without cell cycle inducer, suggesting that prolonged G1 arrest of tubule cells might be partially responsible for persistent M1 mediated inflammation during the recovery phase in aged mice. Finally, M1 predominant renal inflammation in old mice resulted in fibrosis progression on day 28.

Conclusion

Our data show that persistent M1 mediated inflammation driven by adjacent arrested tubule cells is thought to be one of the mechanisms of impaired recovery and progression to CKD in aged mice.