#5349 CYCLIN D1 AMELIORATES ACUTE KIDNEY INJURY BY IMPROVING FATTY ACID OXIDATION VIA AMPK PATHWAY

Abstract

Abstract Background and Aims Acute kidney injury (AKI) is a life-threatening condition. The absence of oxygen during the acute ischemic phase would disturb energy metabolism and cause 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, but 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 found that CCND1 improved AKI accompanied with increased fatty acid oxidation. Therefore, we investigated the role and molecular basis for CCND1 involvement in fatty acid oxidation of AKI. Method CCND1 was evaluated in AKI in human kidney proximal tubular epithelial cells (HK-2 cells) and male C57BL/6J mice (wild type). The protective role of CCND1 in AKI was investigated in a mouse model of ischemia-reperfusion AKI treated by ultrasound-microbubble-mediated kidney-specifically transferring CCND1-expressing plasmids in male C57BL/6J mice (wild type). 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 had shown that activation of CCND1 can prevent 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) lowered the concentrations of blood urea nitrogen and creatinine. Kidney specific overexpression of CCND1 promoted 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 contrary, inhibiting the expression of CCND1 exacerbated impairment of FAO and disturbed energy metabolism. Conclusion Thus, CCND1 improved FAO and reduced lipid accumulation via active AMPK pathway in kidney proximal tubular epithelial cells (PTECs). Hence, reconstruction of the expression of CCND1 may be a novel therapeutic strategy for treating AKI.