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Contrast-induced nephropathy (CIN) is a leading cause of hospital-acquired acute kidney injury (AKI), but detailed pathogenesis and effectual remedy remain elusive. Here, we tested the hypothesis that contrast media (CM) impaired mitochondrial quality control (MQC) in tubules, including mitochondrial fragmentation and mitophagy, induced systemic inflammation, and intestinal injury. Since we previously demonstrated that the natural antioxidant 2,3,5,6-tetramethylpyrazine (TMP) can be a protectant against CIN, we moreover investigated the involved renoprotective mechanisms of TMP. In a well-established CIN rat model, renal functions, urinary AKI biomarkers, and renal reactive oxygen species (ROS) production were measured. Mitochondrial damage and mitophagy were detected by transmission electron microscopy (TEM) and western blot. The abundance of Drp1 and Mfn2 by western blot and immunohistochemistry (IHC) was used to evaluate mitochondrial fragmentation. TUNEL staining, TEM, and the abundance of cleaved-caspase 3 and procaspase 9 were used to assay apoptosis. We demonstrated that increased mitophagy, mitochondrial fragmentation, ROS generation, autophagy, and apoptosis occurred in renal tubular cells. These phenomena were accompanied by renal dysfunction and an increased excretion of urinary AKI biomarkers. Meanwhile, CM exposure resulted in concurrent small intestinal injury and villous capillary endothelial apoptosis. The abundance of the inflammatory cytokines CCL2 and CCR2 markedly increased in the renal tubules of CIN rats, accompanied by increased concentrations of IL-6 and TNF-α in the kidneys and the serum. Interestingly, TMP efficiently prevented CM-induced kidney injury in vivo by reversing these pathological processes. Mechanistically, TMP inhibited the CM-induced activation of the CCL2/CCR2 pathway, ameliorated renal oxidative stress and aberrant mitochondrial dynamics, and modulated mitophagy in tubular cells. In summary, this study demonstrated novel pathological mechanisms of CIN, that is, impairing MQC, inducing CCL2/CCR2-mediated inflammation and small intestinal injury, and provided novel renoprotective mechanisms of TMP; thus, TMP may be a promising therapeutic agent for CIN.

oxidative medicine and cellular longevity

Tetramethylpyrazine Prevents Contrast-Induced Nephropathy via Modulating Tubular Cell Mitophagy and Suppressing Mitochondrial Fragmentation, CCL2/CCR2-Mediated Inflammation, and Intestinal Injury