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.

Delivery of Recombinant Adeno-Associated Virus-Mediated Human Tissue Kallikrein for Therapy of Chronic Renal Failure in Rats

“…In contrast, low doses of dopamine and treatment with D 1 R agonists provide renal protection and have diuretic effects [48]. In addition to hypotensive effects, B 2 R stimulation by bradykinin activates MAP kinases, PI3 kinase/Akt, and JNK signaling pathways to enhance survival and reduce apoptosis [21]. rAAV-mediated delivery of the HK gene markedly upregulated B 2 R and D 1 R and downregulated AT 1 R, ET A R and V 2 R in both in vitro and in vivo experiments in this study.…”

“…Our previous studies documented that rAAV-HK delivery rendered a long-term and stable reduction in hypertension and provided protection against renal injury in the spontaneously hypertensive and the streptozotocin-induced type 2 diabetic rat models [12,19,21]. However, the therapeutic effect of HK on chronic renal failure has not been studied.…”

Recombinant adeno-associated virus-mediated human kallikrein gene therapy prevents high-salt diet-induced hypertension without effect on basal blood pressure1

“…This unique feature can render a long-term and stable expression of the target gene [4][5][6] . Previous studies have shown that a single injection of rAAV-HK gene delivery causes a prolonged reduction of systolic blood pressure in different hypertensive animal models, which makes it possible to treat hypertension through gene therapy [9,17] . However, it remains unknown whether the overexpression of the HK gene can induce hypotension in normotensive rats.…”

“…Its attenuation is suggested as a possible etiological factor in salt-sensitive hypertension [15,16] . Our previous studies have demonstrated that rAAV-HK delivery attenuates the increased blood pressure induced by fructose or streptozotocin in conjunction with a high-fat diet and ameliorates organ injury [17] . However, its effect on high-salt diet-induced hypertension in rats with normal blood pressure remains unknown.…”

Tissue kallikrein deficiency, insulin resistance, and diabetes in mouse and man

“…This hypothesis is further supported by experimental studies documenting improvement mediated by kinins of insulin resistance during ACE inhibitor treatment in obese and diabetic rodent models (Henriksen et al 1999, Shiuchi et al 2002. TK gene therapy has been reported to reverse insulin resistance and attenuate nephropathy in diabetic rats (Yuan et al 2007). Moreover, lack of kininogen or kinin B2 receptor impaired insulin sensitivity and glucose tolerance in nondiabetic animals, indicating that the KKS is involved in insulin action and glucose homeostasis (Damas et al 1999, Duka et al 2001, Kakoki et al 2010.…”