Expert opinion on investigational drugs · 2012
The role of heat shock protein 90 in modulating ischemia-reperfusion injury in the kidney.
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O'Neill Stephen, Ross James A, Wigmore Stephen J, Harrison Ewen M
Аннотация
INTRODUCTION: Kidney transplantation is the gold standard treatment for end-stage renal disease. Ischemia-reperfusion injury (IRI) is an unavoidable consequence of the transplantation procedure and is responsible for delayed graft function and poorer long-term outcomes.
AREAS COVERED: Pharmacological induction of heat shock protein (Hsp) expression is an emerging pre-conditioning strategy aimed at reducing IRI following renal transplantation. Hsp90 inhibition up-regulates protective Hsps (especially Hsp70) and potentially down-regulates NF-κB by disruption of the IκB kinase (IKK) complex. However, the clinical application of Hsp90 inhibitors is currently limited by their toxicity profile and the exact mechanism of protection conferred is unknown. Toll-like receptor 4 (TLR4) is a further regulator of NF-κB and recent studies suggest TLR4 plays a dominant role in mediating kidney damage following IRI. The full interaction of Hsps with TLRs is yet to be delineated and whether TLR4 signalling can be targeted by Hsp90 inhibition in IRI remains uncertain.
EXPERT OPINION: Pharmacological pre-conditioning by Hsp90 inhibition involves direct treatment to the kidney donor and/or organ, which aims to reduce injury prior to the onset of ischemia. The major challenges going forward are to establish the exact mechanism of protection offered by these drugs and the investgiation of less toxic analogues that could be safely translated into human studies.
AREAS COVERED: Pharmacological induction of heat shock protein (Hsp) expression is an emerging pre-conditioning strategy aimed at reducing IRI following renal transplantation. Hsp90 inhibition up-regulates protective Hsps (especially Hsp70) and potentially down-regulates NF-κB by disruption of the IκB kinase (IKK) complex. However, the clinical application of Hsp90 inhibitors is currently limited by their toxicity profile and the exact mechanism of protection conferred is unknown. Toll-like receptor 4 (TLR4) is a further regulator of NF-κB and recent studies suggest TLR4 plays a dominant role in mediating kidney damage following IRI. The full interaction of Hsps with TLRs is yet to be delineated and whether TLR4 signalling can be targeted by Hsp90 inhibition in IRI remains uncertain.
EXPERT OPINION: Pharmacological pre-conditioning by Hsp90 inhibition involves direct treatment to the kidney donor and/or organ, which aims to reduce injury prior to the onset of ischemia. The major challenges going forward are to establish the exact mechanism of protection offered by these drugs and the investgiation of less toxic analogues that could be safely translated into human studies.