CB1 receptor antagonist rimonabant protects against chronic intermittent hypoxia-induced renal injury in rats

Abstract

Background Obstructive sleep apnoea (OSA) induced chronic kidney disease is mainly caused by chronic intermittent hypoxia (CIH). Our study investigate the mechanism underlying CIH-induced renal damage and whether the cannabinoid receptor 1 (CB1R) antagonist rimonabant (Ri) alleviates CIH-induced renal injury. Methods Male Sprague-Dawley rats were randomly divided into five groups: one normal control (NC) group, two chronic intermittent hypoxia (CIH) groups, and two CIH + Ri groups. Rats in the NC groups were exposed to room air, while the CIH groups were exposed to a CIH environment for 4 weeks (4w CIH group) and 6 weeks (6w CIH group), respectively. Additionally, rats in the CIH + Ri groups were administered 1.5 mg/kg/day Ri for 4 weeks (4w CIH + Ri group) and 6 weeks (6w CIH + Ri group), respectively. Following this, the rats were euthanized and kidneys were excised for downstream analysis. In the renal tissues, the morphological alterations were examined via haematoxylin eosin (HE) staining and periodic acid schiff (PAS) staining, CB1R, Fis1, Mfn1, and p66Shc expression was assessed through western blot and immunohistochemistry, and the mitochondrial ultrastructural changes in kidney sections were assessed by electron microscopy. Results CB1R expression in the 4w and 6w CIH groups was significantly elevated, and further increased with prolonged hypoxia; however, Ri prevented the increase in CIH-induced CB1R expression. Fis1 and p66Shc expression in the CIH groups were increased, but Mfn1 expression decreased. Ri decreased Fis1 and p66Shc expression and increased Mfn1 expression. Renal damage in the 4w or 6w CIH + Ri group was evidently improved compared with that in the 4w or 6w CIH group. CB1R expression was positively correlated with Fis1 and p66Shc and negatively correlated with Mfn1. Meanwhile, electron microscopy showed that the percentage of fragmented mitochondria in the tubular cells in each group was consistent with the trend of CB1R expression. Conclusion CIH causes endocannabinoid disorders and induces abnormal mitochondrial dynamics, resulting in renal injury. Treatment with CB1R antagonists reduces CIH-induced renal damage by inhibiting dysregulated renal mitochondrial dynamics.

Aryl Hydrocarbon Receptor and Cysteine Redox Dynamics Underlie (Mal)adaptive Mechanisms to Chronic Intermittent Hypoxia in Kidney Cortex

“…Long-term moderate-to-severe IH (20 to 60 cycles/h. 21–8% O 2 , 35–60 days) induces kidney histological changes [ 64 , 65 ]; increases markers of fibrosis [ 5 , 6 , 65 ], inflammation [ 5 , 6 , 66 , 67 ], oxidative stress [ 3 , 5 , 6 , 66 ], and ER stress [ 3 ]; promotes abnormal mitochondrial dynamics [ 68 ] and cell apoptosis [ 3 , 5 , 6 , 64 , 67 ]; increases growth factors [ 64 ], noradrenaline [ 65 ] and Ang II concentrations [ 6 ]; stabilizes Hif1α [ 5 ] and increases serum Cr and blood urea nitrogen (BUN) levels [ 67 ] and albuminuria [ 64 ]. It is important to note that the aforementioned studies were performed in long-term moderate and severe IH rodent models.…”

Bcl-2 19-kDa Interacting Protein 3 (BNIP3)-Mediated Mitophagy Attenuates Intermittent Hypoxia-Induced Human Renal Tubular Epithelial Cell Injury

“…Intermittent hypoxia (IH), one of the novel pathophysiological characteristics of OSA, can result in several physiological changes, including systemic inflammation, endothelial dysfunction, oxidative stress, and apoptosis. Experimental studies proved that IH causes renal damage, inducing high renal oxidative stress [ 7 ] and apoptosis levels [ 8 – 10 ], and abnormal mitochondrial dynamics [ 11 ]. Consistent with previous studies, a study by our team confirmed that chronic IH contributed to high protein levels associated with autophagy and apoptosis in mice mimicking OSA [ 12 ].…”

Considerations for Cannabinoids in Perioperative Care by Anesthesiologists

“…It was briefly approved as an antiobesity medication, but it was withdrawn due to serious side effects, including psychosis. Currently, this active compound has only experimental application [108].…”