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Tissue Kallikrein Reverses Insulin Resistance and Attenuates Nephropathy in Diabetic Rats by Activation of Phosphatidylinositol 3-Kinase/Protein Kinase B and Adenosine 5'-Monophosphate-Activated Protein Kinase Signaling Pathways

Department of Internal Medicine and Gene Therapy Center (G.Y., J.D., T.W., C.Z., X.Xu., P.W., X.Xi., D.W.W.), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, People’s Republic of China; Division of Intramural Research (J.W.V., M.L.E., D.C.Z.), National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina 27709; Departments of Molecular Genetics and Biochemistry and Gene Therapy Center (X.Xi.), University of Pittsburgh, Pittsburgh, Pennsylvania 15260; Department of Biochemistry and Molecular Biology (L.C., J.C.), Medical University of South Carolina, Charleston, South Carolina 29425; and Vascular Biology Center and Departments of Medicine and Molecular Science (X.A.Z.), University of Tennessee Health Science Center, Memphis, Tennessee 38163

Address all correspondence and requests for reprints to: Dao Wen Wang, M.D., Ph.D., Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan 430030, People’s Republic of China. E-mail: dwwang{at}tjh.tjmu.edu.cn.

We previously reported that iv delivery of the human tissue kallikrein (HK) gene reduced blood pressure and plasma insulin levels in fructose-induced hypertensive rats with insulin resistance. In the current study, we evaluated the potential of a recombinant adeno-associated viral vector expressing the HK cDNA (rAAV-HK) as a sole, long-term therapy to correct insulin resistance and prevent renal damage in streptozotocin-induced type-2 diabetic rats. Administration of streptozotocin in conjunction with a high-fat diet induced systemic hypertension, diabetes, and renal damage in rats. Delivery of rAAV-HK resulted in a long-term reduction in blood pressure, and fasting plasma insulin was significantly lower in the rAAV-HK group than in the control group. The expression of phosphatidylinositol 3-kinase p110 catalytic subunit and the levels of phosphorylation at residue Thr-308 of Akt, insulin receptor B, and AMP-activated protein kinases were significantly decreased in organs from diabetic animals. These changes were significantly attenuated after rAAV-mediated HK gene therapy. Moreover, rAAV-HK significantly decreased urinary microalbumin excretion, improved creatinine clearance, and increased urinary osmolarity. HK gene therapy also attenuated diabetic renal damage as assessed by histology. Together, these findings demonstrate that rAAV-HK delivery can efficiently attenuate hypertension, insulin resistance, and diabetic nephropathy in streptozotocin-induced diabetic rats.