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.

Abstract

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.

• Authors: Gang Yuan, Juanjuan Deng, Tao Wang, Chunxia Zhao, Xizheng Xu, Peihua Wang, James W Voltz, Matthew L Edin, Xiao Xiao, Lee Chao, Julie Chao, Xin A Zhang, Darryl C Zeldin, Dao Wen Wang
• Journal: Endocrinology (Endocrinology) Vol. 148 Issue 5 Pg. 2016-26 (May 2007) ISSN: 0013-7227 [Print] United States
• PMID: 17272402 (Publication Type: Journal Article, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't)

Chemical References

• Multienzyme Complexes
• Protein Serine-Threonine Kinases
• Proto-Oncogene Proteins c-akt
• Mitogen-Activated Protein Kinase 1
• Mitogen-Activated Protein Kinase 3
• AMP-Activated Protein Kinases
• Tissue Kallikreins

Topics

• AMP-Activated Protein Kinases
• Animals
• Apoptosis
• Blood Pressure
• Diabetes Mellitus, Experimental (complications, therapy)
• Diabetes Mellitus, Type 2 (complications, therapy)
• Diabetic Nephropathies (pathology, therapy)
• Gene Expression
• Genetic Therapy (methods)
• Humans
• Hyperinsulinism (pathology, therapy)
• Insulin Resistance
• Male
• Mitogen-Activated Protein Kinase 1 (metabolism)
• Mitogen-Activated Protein Kinase 3 (metabolism)
• Multienzyme Complexes (metabolism)
• Phosphatidylinositol 3-Kinases (metabolism)
• Protein Serine-Threonine Kinases (metabolism)
• Proto-Oncogene Proteins c-akt (metabolism)
• Rats
• Rats, Wistar
• Signal Transduction (physiology)
• Tissue Kallikreins (genetics)