acute knockdown of uncoupling protein-2 increases uncoupling via the adenine nucleotide transporter and decreases oxidative stress in diabetic kidneys急性击倒的解偶联protein-2增加解偶联通过腺嘌呤核苷酸运输车,减少氧化应激在糖尿病肾脏.pdfVIP

Acute Knockdown of Uncoupling Protein-2 Increases Uncoupling via the Adenine Nucleotide Transporter and Decreases Oxidative Stress in Diabetic Kidneys 1,2 2 1 2 2 Malou Friederich-Persson *, Shakil Aslam , Lina Nordquist , William J. Welch , Christopher S. Wilcox , Fredrik Palm1,3 1 Division of Integrative Physiology, Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden, 2 Division of Nephrology and Hypertension, Department of Medicine, Kidney and Vascular Research Centre, Georgetown University Medical Center, Washington, D.C., United States of America, 3 Department of Medical Health Sciences, Linkoping University, Linkoping, Sweden Abstract Increased O2 metabolism resulting in chronic hypoxia is common in models of endstage renal disease. Mitochondrial uncoupling increases O2 consumption but the ensuing reduction in mitochondrial membrane potential may limit excessive oxidative stress. The present study addressed the hypothesis that mitochondrial uncoupling regulates mitochondria function and oxidative stress in the diabetic kidney. Isolated mitochondria from kidney cortex of control and streptozotocin- induced diabetic rats were studied before and after siRNA knockdown of uncoupling protein-2 (UCP-2). Diabetes resulted in increased UCP-2 protein expression and UCP-2-mediated uncoupling, but normal mitochondria membrane potential. This uncoupling was inhibited by GDP, which also increased the membrane potential. siRNA reduced UCP-2 protein expression in controls and diabetics (230–50%), but paradoxically further increased uncoupling and markedly reduced the membrane potential. This siRNA mediated un