AAV-mediated gene therapy for renal tubulointerstitial fibrosis

Fibrotic processes in chronic kidney diseases are the leading cause of renal failure. Hepatocyte growth factor (HGF), effecting organ restructuring by its mitogenic, motogenic, morphogenic and anti-apoptotic activities, is one of the central mediators involved in tubular repair and regeneration after acute renal injury. In addition, HGF acts as an anti-inflammatory and anti-fibrotic factor antagonizing pro-fibrotic actions of transforming growth factor β (TGFβ). However, the molecular and cellular mechanisms underlying the anti-fibrotic function of HGF in chronic kidney disease are not well understood. Therefore, in the present study HGF signaling and HGF induced expression profiles were studied in renal interstitial fibroblasts that represent a central cell type in tubulointerstitial fibrosis due to their prominent production of extracellular matrix proteins. Furthermore, gene therapeutical HGF application using different serotypes of the adeno-associated viral vector (AAV), namely AAV2, AAV8 and AAV9, was tested in order to treat tubulointerstitial fibrosis in a COL4A3 knockout mouse model.