Tissue Kallikrein Reverses Insulin Resistance and Attenuates Nephropathy in Diabetic Rats by Activation of PI3 kinase/Akt and AMPK Signaling Pathways

摘要

We previously reported that intravenous 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 PI3-kinase p110 catalytic subunit, and the levels of phosphorylation at residue Thr-308 of Akt, insulin receptor B and AMP-activated protein kinases (AMPK) were significantly decreased in organs from diabetic animals. These changes were significantly attenuated following 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.