Abstract
Recently, hydrodynamic gene delivery has been demonstrated as a viable method to manipulate adaptive changes in mitochondria, by up regulating specific gene activity that confers protection against ischemic damage. As a means of extending the method's utility, we examined its ability to reliably introduce transgenes after ischemic injury has been established. Renal injury was generated in rats using bilateral renal pedicle cross clamps to occlude blood flow for periods of 10-15 and 30-45 minutes. These clamp periods correspond to mild and moderate/acute kidney injuries respectively. At the end of each injury period, the clamps were removed to reinstate renal blood flow and the animals were prepared to receive hydrodynamic delivery of EGFP plasmid reporters at either 1 or 24 hours after ischemia/reperfusion injury. Remarkably, pressurized renal vein injections of plasmid DNA produced robust and targeted exogenous protein expression in this renal injury model. Intravital two-photon microscopy revealed 60-90% transfection efficiency rates and substantial levels of fluorescent transgene expression in proximal tubules, which is the site of major damage during AKI, after administering injections at both the 1- and 24-hour time points. These results show that hydrodynamic delivery of transgenes can be performed in kidneys recovering from ischemia reperfusion injury.
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