Mice that overexpress human heat shock protein 27 have increased renal injury following ischemia reperfusion

Kevin Brown,Mihwa Kim,Vivette D. D'Agati,Minjae Kim,H. Thomas Lee,Joseph H. Song,Sean W.C. Chen,Jacqueline de Belleroche,Dominic Wells,Sang Won Park

doi:10.1038/ki.2008.572

Kevin Brown, Mihwa Kim

Open Access

https://doi.org/10.1038/ki.2008.572

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Journal: Kidney International	Publication Date: Mar 1, 2009
Citations: 34	License type: publisher-specific-oa

Affiliation: Columbia University, Imperial College London

Abstract

We previously showed that activation of the A1 adenosine receptor protected the kidney against ischemia-reperfusion injury by induction and phosphorylation of heat shock protein 27 (HSP27). Here, we used mice that overexpress human HSP27 (huHSP27) to determine if kidneys from these mice were protected against injury. Proximal tubule cells cultured from the transgenic mice had increased resistance to peroxide-induced necrosis compared to cells from wild-type mice. However, after renal ischemic injury, HSP27 transgenic mice had decreased renal function compared to wild-type mice, along with increased renal expression of mRNAs of pro-inflammatory cytokines (TNF-alpha, ICAM-1, MCP-1) and increased plasma and kidney keratinocyte-derived cytokine. Following ischemic injury, neutrophils infiltrated the kidneys earlier in the transgenic mice. Flow cytometric analysis of lymphocyte subsets showed that those isolated from the kidneys of transgenic mice had increased CD3(+), CD4(+), CD8(+), and NK1.1(+) cells 3 h after injury. When splenocytes or NK1.1(+) cells were isolated from transgenic mice and adoptively transferred into wild-type mice there was increased renal injury. Further, depletion of lymphocytes by splenectomy or neutralization of NK1.1(+) cells resulted in improved renal function in the transgenic mice following reperfusion. Our study shows that induction of HSP27 in renal tubular cells protects against necrosis in vitro, but its systemic increase counteracts this protection by exacerbating renal and systemic inflammation in vivo.

Highlights

Acute renal failure (ARF) is a disease characterized by high patient morbidity and mortality.[1,2,3] Despite considerable research, there is no effective therapy for ARF.[1]
We have previously shown that A1AR activation phosphorylates heat shock protein 27 (HSP27) in cultured renal proximal tubule cells and chronic activation or overexpression (OE) of A1ARs leads to upregulation of total HSP27.11 This finding was replicated in vivo, as mice treated with a selective A1AR agonist, 2-chloro-N6-cyclopentyladenosine, before renal ischemia showed a reduction in renal corticomedullary necrosis, apoptosis, and inflammation that corresponded with an increase in HSP27 expression.[12]
Renal proximal tubules cultured from the human HSP27 (huHSP27) OE mice showed increased resistance against H2O2-induced necrosis with reduced lactate dehydrogenase released when compared to the HSP27 WT mice proximal tubules (Figure 2)

Summary

Introduction

Acute renal failure (ARF) is a disease characterized by high patient morbidity and mortality.[1,2,3] Despite considerable research, there is no effective therapy for ARF.[1]. We have previously shown that A1AR activation phosphorylates heat shock protein 27 (HSP27) in cultured renal proximal tubule cells and chronic activation or overexpression (OE) of A1ARs leads to upregulation of total HSP27.11 This finding was replicated in vivo, as mice treated with a selective A1AR agonist, 2-chloro-N6-cyclopentyladenosine, before renal ischemia showed a reduction in renal corticomedullary necrosis, apoptosis, and inflammation that corresponded with an increase in HSP27 expression.[12]. HSP27 is a potent antiapoptotic protein and is a key stabilizer of the actin cytoskeleton; both of these cellular effects lead to increased resistance against cell death.[20,21,22] Not surprisingly, OE of HSP27 protected against neuronal and cardiac injury.[23,24,25]

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