Adenoviral delivery of the β2-adrenoceptor gene in sepsis: a subcutaneous approach in rat for kidney protection

Abstract

Successful gene therapy requires gene delivery that is efficient, has an optimal route of administration and has biosafety. The aims of the present study were to evaluate the safety and applicability of the subcutaneous delivery route for adenoviral transgenes containing the human beta(2)-adrenoceptor (adeno-beta(2)-AR) and to investigate whether this approach prevented renal dysfunction in a rat model of endotoxaemic shock induced by LPS (lipopolysaccharide). Subcutaneous administration of adeno-beta(2)-AR (a total of 10(10) viral particles) significantly increased beta-AR density in the kidney, lung and liver, but was without effect on physiological and plasma biochemical parameters. Moreover, this dose of virus did not cause any of the potential toxic responses of viral administration, such as inflammation and tissue TNF (tumour necrosis factor)-alpha expression. Although the LPS challenge caused a decrease in glomerular filtration rate, fractional excretion of sodium and renal beta-AR density in all groups, the reduction in renal function was significantly less in the rats given adeno-beta(2)-AR compared with non-treated rats. Thus, although further evaluation will be required, this initial study demonstrated that the subcutaneous injection of adeno-beta(2)-AR was efficient, comparatively non-pathogenic and potentially therapeutic to deal with acute renal failure associated with sepsis.

Proximal Tubule β2-Adrenergic Receptor Mediates Formoterol-Induced Recovery of Mitochondrial and Renal Function after Ischemia-Reperfusion Injury

“…We demonstrated that RPTC b 2 AR is responsible for the effects of formoterol on renal function after AKI. Previous studies in septic AKI demonstrated that overexpression or activation of the b 2 AR by terbutaline prevents apoptosis, decreases injury, and promotes recovery of renal function (Nakamura et al, 2003(Nakamura et al, , 2004(Nakamura et al, , 2005(Nakamura et al, , 2010; however, in these studies, excessive activation of the b 2 AR decreased serum creatinine (Nakamura et al, 2007). We have shown that selective and limited activation of the b 2 AR by formoterol accelerates recovery from IR-induced AKI (Jesinkey et al, 2014), and in these studies, we have shown that formoterol does so by activating RPTC b 2 AR.…”

Still Finding Ways to Augment the Existing Management of Acute and Chronic Kidney Diseases with Targeted Gene and Cell Therapies: Opportunities and Hurdles

“…Over the past 30 years, many methods have been proposed to deliver exogenous genes and cells to target organs [31,38,45,95,98,100,128,140,[147][148][149][150][151][152][153][154][155]. From a fundamental viewpoint, these techniques seek to provide inexpensive and rapid alternatives to pronuclear microinjection-derived transgenic models and platforms for translational studies [119].…”

“…Several reports have indicated inconsistent outcomes regarding the effectiveness of existing gene and cell transfer techniques. Studies in the kidney have illustrated this variability [153,154,[156][157][158][159][160][161][162]. In general, an in vivo gene and cell transfer system's success relies on various factors.…”

Still finding ways to augment the existing management of acute and chronic kidney diseases with targeted gene and cell therapies: Opportunities and hurdles

“…Over the past 30 years, many methods have been proposed to deliver exogenous genes and cells to target organs (32,39,46,97,100,102,130,142,(149)(150)(151)(152)(153)(154)(155)(156)(157). From a fundamental viewpoint, these techniques seek to provide inexpensive and rapid alternatives to pronuclear microinjection-derived transgenic models and platforms for translational studies (121).…”

“…Several reports have indicated inconsistent outcomes regarding the effectiveness of existing gene and cell transfer techniques. Studies in the kidney have illustrated this variability ( 155 , 156 , 158 – 164 ). In general, an in vivo gene and cell transfer system’s success relies on various factors.…”