Dexmedetomidine attenuation of renal ischaemia-reperfusion injury requires sirtuin 3 activation

Dexmedetomidine attenuates renal ischaemia and reperfusion (I/R) injury, but its mechanism of action is unclear. As sirtuin 3 (SIRT3) activation can alleviate acute kidney injury, we investigated whether dexmedetomidine acts through SIRT3 to reduce renal I/R injury.

The potential involvement of SIRT3 in dexmedetomidine attenuation of renal I/R injury was tested in HK2 cells subjected to hypoxia/reoxygenation and C57BL/6J mice subjected to renal I/R. A short interfering RNA targeting SIRT3 was used in some experiments to examine the potential role of SIRT3. Cell death and mitochondrial membrane potential (Δψm) were analysed in cultured cells. Mitochondrial damage in mice was assessed using electron microscopy and markers for renal function. Expression of cyclophilin D, cytochrome c, and SIRT3, and the level of cyclophilin D acetylation were determined.

Hypoxia/reoxygenation of HK2 cells increased cell death, cytochrome C expression, and cyclophilin D acetylation, and decreased Δψm and SIRT3 expression (P<0.05). Dexmedetomidine attenuated these changes. The dexmedetomidine effects were enhanced by SIRT3 overexpression and eliminated by SIRT3 knockdown. I/R in mice damaged renal function, and increased histological lesions, mitochondrial damage, cytochrome c expression, and cyclophilin D acetylation, while SIRT3 activity was decreased by 51% (P<0.05). Dexmedetomidine inhibited these changes in mice expressing normal levels of SIRT3, but not in SIRT3-knockdown mice.

Dexmedetomidine appears to act, at least in part, by up-regulating SIRT3 to inhibit mitochondrial damage and cell apoptosis and thereby protect against renal I/R injury.