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J Am Soc Nephrol 14:947-958, 2003
© 2003 American Society of Nephrology

Gene Delivery in Renal Tubular Epithelial Cells Using Recombinant Adeno-Associated Viral Vectors

Sifeng Chen*, Anupam Agarwal*, Olena Y. Glushakova*, Marda S. Jorgensen{dagger}, Shashikumar K. Salgar{ddagger}, Amy Poirier§, Terence R. Flotte§, Byron P. Croker{dagger},¶, Kirsten M. Madsen*, Mark A. Atkinson{dagger}, William W. Hauswirth#, Kenneth I. Berns# and C. Craig Tisher*

*Departments of Medicine, {dagger}Pathology, §Pediatrics, #Molecular Genetics and Microbiology, University of Florida, Gainesville, Florida; Pathology and Laboratory Medicine Service, Malcolm Randall VA Medical Center, Gainesville, Florida; and {ddagger}Department of Surgery, University of Miami, Miami, Florida.

Correspondence to Dr. Anupam Agarwal, Associate Professor of Medicine, Division of Nephrology, Hypertension and Transplantation, Box 100224 JHMHC, 1600 SW Archer Road, University of Florida, Gainesville FL 32610. Phone: 352-846-2367; Fax: 352-392-3581;

ABSTRACT. Gene therapy has the potential to provide a therapeutic strategy for numerous renal diseases such as diabetic nephropathy, chronic rejection, Alport syndrome, polycystic kidney disease, and inherited tubular disorders. In previous studies using cationic liposomes or adenoviral or retroviral vectors to deliver genes into the kidney, transgene expression has been transient and often associated with adverse host immune responses, particularly with the use of adenoviral vectors. The unique properties of recombinant adeno-associated viral (rAAV) vectors permit long-term stable transgene expression with a relatively low host immune response. The purpose of the present study was to evaluate gene expression in the rat kidney after intrarenal arterial infusion of a rAAV (serotype 2) vector encoding green fluorescence protein (GFP) induced by a cytomegalovirus-chicken beta-actin hybrid promoter. The left kidney of experimental animals was treated with either saline or transduced with rAAV2-GFP (0.125 ml/100 g body wt, 1 x 1010/ml infectious units) through the renal artery. A time-dependent expression of GFP was observed in all kidneys injected with rAAV2-GFP, with maximal expression observed at 6 wk posttransduction. The expression of GFP was restricted to cells in the S3 segment of the proximal tubule and intercalated cells in the collecting duct, the latter identified by co-localization with H+-ATPase. No transduction was observed in the glomeruli or the intrarenal vasculature. These studies demonstrate successful transgene expression in tubular epithelial cells, specifically in the S3 segment of the proximal tubule and intercalated cells, after intrarenal administration of a rAAV vector and provide the impetus for further studies to exploit its use as a tool for gene therapy in the kidney.

E-mail: agarwal@nersp.nerdc.ufl.edu




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