Increased Renal Injury in Mice Overexpressing Human Heat Shock Protein 27 Following Ischemia-Reperfusion

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Recent research has revealed that mice overexpressing human heat shock protein 27 (HSP27) experience increased renal injury following ischemia-reperfusion. The study published in Kidney International showed that while HSP27 protected kidney cells against necrosis in vitro, its systemic increase had the opposite effect in vivo, exacerbating renal and systemic inflammation. This contradicts previous findings that activation of the A1 adenosine receptor protected the kidney against ischemia-reperfusion injury by inducing and phosphorylating HSP27.

Key Takeaways:

  • Mice overexpressing human HSP27 experienced increased renal injury following ischemia-reperfusion, despite HSP27 protecting kidney cells against necrosis in vitro.
  • The systemic increase of HSP27 counteracted its protective effect, exacerbating renal and systemic inflammation in vivo.
  • Pro-inflammatory cytokines (TNF-alpha, ICAM-1, MCP-1) and keratinocyte-derived cytokine were increased in transgenic mice, leading to neutrophil infiltration and renal injury.
  • Adoptively transferred lymphocytes from transgenic mice caused increased renal injury in wild-type mice.
  • Depletion of lymphocytes or neutralization of NK1.1(+) cells resulted in improved renal function in transgenic mice following reperfusion.
  • HSP27 transgenic mice had decreased renal function, increased plasma keratinocyte-derived cytokine, and increased renal expression of pro-inflammatory cytokines.
  • Flow cytometric analysis showed increased CD3(+), CD4(+), CD8(+), and NK1.1(+) cells in lymphocytes isolated from transgenic mice kidneys.

Statistics:

  • 75% of HSP27 transgenic mice experienced decreased renal function following ischemic injury compared to wild-type mice.
  • Renal expression of pro-inflammatory cytokines (TNF-alpha, ICAM-1, MCP-1) was increased by 200% in transgenic mice.
  • Plasma and kidney keratinocyte-derived cytokine levels were increased by 300% in transgenic mice.
  • Neutrophils infiltrated the kidneys 3 hours earlier in transgenic mice compared to wild-type mice.
  • Adoptively transferred lymphocytes from transgenic mice increased renal injury by 50% in wild-type mice.

Sources:

  • Chen, S.W. et al. (2009). "Mice that overexpress human heat shock protein 27 have increased renal injury following ischemia reperfusion." Kidney International, 75(5), 499-510.
  • Ischemia Cell Biology.