Abstract
Abstract Background and Aims Acute Kidney Injury (AKI) is a critical condition that is caused by the absence of oxygen during the acute ischemic phase, leading to energy metabolism disturbance and kidney tubular epithelial cell damage. Fatty Acid Oxidation (FAO) is the main source of energy production of renal proximal tubular epithelial cells. Timely promoting FAO, increasing supplies of energy, and promoting cell proliferation are essential to improve kidney injury. However, there is no clinically recognized effective treatment for this. Cyclin D1(CCND1), a member of the cell cycle family, plays a vital role in cell proliferation. Our previous study showed that CCND1 improved AKI by increasing FAO. This study aimed to investigate the role and molecular basis of CCND1 involvement in fatty acid oxidation of AKI. Method CCND1 was evaluated in human kidney proximal tubular epithelial cells (HK-2 cells) and in male C57BL/6J mice (wild type). We investigated the protective role of CCND1 in AKI using a mouse model of ischemia-reperfusion injury, which was treated by transferring CCND1-expressing plasmids in male C57BL/6J mice (wild type) by ultrasound and microbubble-mediated delivery. Eight-week-old male C57BL/6J mice (wild type) were subjected to bilateral renal artery occlusion for 30min followed by 24h of reperfusion. We evaluated FAO, proliferation, and autophagy in vitro and in vivo. In addition, we evaluated the concentrations of blood urea nitrogen and creatinine, evaluated kidney ultrastructure and so on. Results In vivo studies showed that activation of CCND1 prevented AKI-induced lipid accumulation, kidney tubule injury and kidney function declined after ischemia-reperfusion injury. Compared to test control, the treatment significantly (p<0.05) reduced the concentrations of blood urea nitrogen and creatinine. Kidney-specific overexpression of CCND1 increased FAO, promoted proliferation and reduced apoptosis. Mechanistically, CCND1 activated the AMPK pathway, which increased the expression of phosphorylation AMP activated protein kinase (p-AMPK) and upregulated FAO. On the other hand, inhibiting the expression of CCND1 worsened the impairment of FAO and disturbed energy metabolism. Conclusion CCND1 improved FAO and reduced lipid accumulation through the active AMPK pathway in kidney proximal tubular epithelial cells (PTECs). Hence, restoring of the expression of CCND1 may offer a novel therapeutic strategy for treating AKI.
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