Ischemia-reperfusion (I/R) injury is a serious clinical pathology associated with acute kidney injury (AKI). Ferroptosis is non-apoptotic cell death that is known to contribute to renal I/R injury. Dexmedetomidine (Dex) has been shown to exert anti-inflammatory and organ protective effects. This study aimed to investigate the detailed molecular mechanism of Dex protects kidneys against I/R injury through inhibiting ferroptosis. We established the I/R-induced renal injury model in mice, and OGD/R induced HEK293T cells damage in vitro. RNA-seq analysis was performed for identifying the potential therapeutic targets. RNA-seq analysis for differentially expressed genes (DEGs) reported Acyl-CoA synthetase long-chain family member 4 (ACSL4) related to ferroptosis and inflammation in I/R mice renal, which was validated in rodent renal. Liproxstatin-1, the specific small-molecule inhibitor of ferroptosis, significantly attenuated ferroptosis-mediated renal I/R injury with decreased LPO, MDA, and LDH levels, and increased GSH level. Inhibiting the activity of ACSL4 by the Rosiglitazone (ROSI) resulted in the decreased ferroptosis and inflammation, as well as reduced renal tissue damage, with decreasing LPO, MDA and LDH level, increasing GSH level, reducing COX2 and increasing GPx4 protein expression, and suppressing the TNF-α mRNA and IL-6 mRNA levels. Dex as a α2-adrenergic receptor (α2-AR) agonist performed renal protective effects against I/R-induced injury. Our results also revealed that Dex administration mitigated tissue damage, inhibited ferroptosis, and downregulated inflammation response following renal I/R injury, which were associated with the suppression of ACSL4. In addition, ACSL4 overexpression abolishes Dex-mediated protective effects on OGD/R induced ferroptosis and inflammation in HEK293T cells, and promotion of ACSL4 expression by α2-AR inhibitor significantly reversed the effects on the protective role of Dex. This present study indicated that the Dex attenuates ferroptosis-mediated renal I/R injury and inflammation by inhibiting ACSL4 via α2-AR.

This randomized clinical trial compares outcomes among patients who received a donated-after-cardiac-death kidney allograft and either dexmedetomidine or placebo during and after the surgical procedure.

Background Multiple neonatal exposures to sevoflurane induce neurocognitive dysfunctions in rodents. The lack of cell-type specific information following sevoflurane exposure limits the mechanistic understanding of these effects. In this study, we tested the hypothesis that sevoflurane exposures alter the atlas of hippocampal cell clusters and have neuronal and non-neuronal cell-type specific effects in mice of both sexes. Methods Neonatal mice were exposed to 3% sevoflurane for 2 hours at postnatal days 6, 8, and 10 and analysed for the exposure effects at postnatal day 37. Single-nucleus RNA sequencing was performed in the hippocampus followed by in situ hybridization to validate the results of RNA sequencing. Morris Water Maze test was performed to test neurocognitive function. Results We found sex-specific distribution of hippocampal cell types in control mice alongside cell-type- and sex-specific effects of sevoflurane exposure on distinct hippocampal cell populations. There were important changes in male but not in female mice following sevoflurane exposure regarding the proportions of CA1 neurons (control vs sevoflurane, males: 79.9% vs 32.3%; females: 27.3% vs 24.3%), dentate gyrus (males: 4.2% vs 23.4%; females: 36.2% vs 35.8%), and oligodendrocytes (males: 0.6% vs 6.9%; females: 5.9% vs 7.8%). In male but not in female mice, sevoflurane altered the number of significantly enriched ligand-receptor pairs in the CA1, CA3 and dente gyrus trisynaptic circuit (control vs sevoflurane, CA1-CA3: 18 vs 42 in males and 15 vs 21 in females; CA1-dentate gyrus: 21 vs 35 in males and 12 vs 20 in females; CA3-dentate gyrus: 25 vs 45 in males and 17 vs 20 in females), interfered with dentate gyrus granule cell neurogenesis, hampered microglia differentiation, and decreased CA1 pyramidal cell diversity. Oligodendrocyte differentiation was specifically altered in females with increased expressions of Mbp and Mag. In situ hybridization validated the increased expression of common differentially expressed genes. Conclusions This single-nucleus RNA sequencing study reveals the hippocampal atlas of mice, providing a comprehensive resource for the neuronal and non-neuronal cell-type- and sex-specific effects of sevoflurane during development.