Ceria nanoparticles prophylactic used for renal ischemia-reperfusion injury treatment by attenuating oxidative stress and inflammatory response

Abstract

Renal ischemia-reperfusion (IR) injury (RIRI) is the leading cause of acute kidney injury (AKI), a common disease with high morbidity and mortality. However, due to the lack of effective diagnostic and therapeutic tools, patients have to resort to conservative treatment. To address this issue, we have developed a novel prophylactic strategy that involves the pre-treatment use of ceria nanoparticles (CNPs) before surgery. Based on our careful study of the three different sizes of CNPs that we synthesized, 46 nm (NP46), 81 nm (NP81), and 118 nm (NP118), we have found that NP118 can be used as effective prophylactic agents against RIRI and subsequent renal fibrosis. In our experiments, the CNPs exhibited excellent antioxidant and anti-inflammatory activities in vitro and effectively protected the kidney against RIRI and renal fibrosis in vivo, as proved by the decreases in renal lesions, serum creatinine, blood urea nitrogen, apoptotic cell, KIM-1 expression, and fibrotic area in CNPs treated samples relative to RIRI group. Mechanistically, not only did the CNPs reduce oxidative stress by regulating the Nrf2 pathway, but they also attenuated RIRI induced inflammatory response by decreasing macrophage infiltration and polarization to M1 phenotype, and reducing pro-inflammatory cytokine and chemokine production. In vitro results further confirmed that CNPs pre-treatment not only dramatically decreased intracellular ROS production in renal tubular epithelial cells and vascular endothelial cells, but also effectively attenuated lipopolysaccharide-induced inflammation in RAW264.7 cells. In addition, we found that one fourth of the NP118 persisted for more than 21 days in IR kidneys, and that out of the three sizes of CNPs, NP118 achieved the best results in all our experiments. Our study provides new insights into the usage and majorization of CNPs as a potential therapy to treat or prevent RIRI and renal fibrosis.