Ramelteon attenuates renal ischemia and reperfusion injury through reducing mitochondrial fission and fusion and inflammation.

Abstract

Renal ischemia-reperfusion injury (IRI) is a common cause of acute kidney injury (AKI). This study explored the function and mechanisms of ramelteon on IRI-induced AKI. Mice were randomly divided into five groups: Sham, IRI, IRI + ramelteon (0.3 mg/kg), IRI + ramelteon (1 mg/kg), and IRI + ramelteon (3 mg/kg). Mice were intraperitoneally treated with ramelteon for 7 days before IRI. IRI was accomplished by bilateral renal artery clamping for 30 minutes, after which the clamps were removed for blood reperfusion. HK-2 cells were randomly divided into five groups: control, hypoxia/reoxygenation (H/R), H/R + ramelteon (10 nM), H/R + ramelteon (30 nM), and H/R + ramelteon (60 nM). HK-2 cells were prophylactically treated with ramelteon and then exposed to H/R. Ramelteon attenuated renal injury, inhibited cell apoptosis, decreased reactive oxygen species (ROS) generation, and suppressed levels of interleukin 6 (IL-6), tumor necrosis factor-α (TNF-α), and interleukin 1β (IL-1β). Ramelteon decreased apoptosis-related protein Bax and TLR4-related proteins (TLR4, MyD88, p-IκBα, and p-p65 NF-κB), enhanced apoptosis-related protein Bcl-2. Furthermore, ramelteon increased mitochondrial membrane potential in H/R cells. Mitochondrial-related proteins (Drp1, Fis1, and Mff) were abated, whereas Mfn1 and Mfn2 were enhanced in H/R induced cells. Ramelteon attenuates renal injury induced by IRI and H/R, which is involved in apoptosis, mitochondrial damage, and inflammation.