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

Abstract

Background: 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. Methods: 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 (Djm) 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. Results: Hypoxia/reoxygenation of HK2 cells increased cell death, cytochrome C expression, and cyclophilin D acetylation, and decreased Djm 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. Conclusions: 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.

Dexmedetomidine alleviates cisplatin‑induced acute kidney injury by attenuating endoplasmic reticulum stress‑induced apoptosis via the α2AR/PI3K/AKT pathway

“…using Pi3K-knockout mice, it was previously revealed that a conventional dose of cP was more lethal in these knockout mice, indicating the importance of the Pi3K/aKT pathway in protecting the kidneys (21). dexmedetomidine (dex), a highly selective α 2 adrenoreceptor (α 2 AR) agonist, has been reported to be beneficial for the prevention of numerous types of kidney diseases, including acute stress-induced kidney injury (22), ischemia-reperfusion and sepsis-induced kidney injuries (23)(24)(25). it has also been demonstrated that dex protects the kidney against cP-induced AKI by regulating apoptosis and the inflammatory response (26).…”

Pretreatment with dexmedetomidine alleviates lung injury in a rat model of intestinal ischemia reperfusion

“…deX was approved by the uS Food and drug administration in 1999 and has been used for analgesia and sedation in intensive care units (29). in animal studies, it has been demonstrated to inhibit oxidative stress and inflammatory responses to protect the kidneys, brain, intestine and heart from ischemia-reperfusion injury (16,(30)(31)(32)(33)(34). However, to the best of our knowledge, few studies have focused on deX on iir-induced lung injury.…”

Protein acetylation and deacetylation: An important regulatory modification in gene transcription (Review)

“…In addition, oxidative stress and mitochondrial function of renal tubular epithelial cells tend to be ameliorated (155). Also, dexmedetomidine plays a role in treating AKI because it induces the upregulation SIRT3 (162).…”