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Pathophysiology of Renal Disease and Progression |
* Division of Nephrology, Department of Pediatrics, Powell Gene Therapy Center, and Genetics Institute, Departments of Ophthalmology and Molecular Genetics and Microbiology, and || Department of Pathology, University of Florida, Gainesville, Florida; Division of Nephrology, University of Alabama, Birmingham, Alabama; and ¶ Division of Nephrology, University of Maracaibo, Maracaibo, Venezuela
Address correspondence to: Dr. Wei Mu, Division of Nephrology, University of Florida, P.O. Box 100224, Gainesville, FL 32610. Phone: 352-392-3677; Fax: 352-392-5465; E-mail muw{at}medicine.ufl.edu
Received for publication March 17, 2005. Accepted for publication September 14, 2005.
IL-10 is a pluripotent cytokine that plays a pivotal role in the regulation of immune and inflammatory responses. Whereas short-term administration of IL-10 has shown benefit in acute glomerulonephritis, no studies have addressed the potential benefits of IL-10 in chronic renal disease. Chronically elevated blood levels of IL-10 in rats were achieved by administration of a recombinant adeno-associated virus serotype 1 IL-10 (rAAV1–IL-10) vector. Control rats were given a similar dose of rAAV1-GFP. Four weeks after injection, IL-10 levels in serum were measured by ELISA, and chronic renal disease was induced by a 5/6 nephrectomy (n = 6 in each group). Eight weeks later, rats were killed and renal tissue was obtained for RNA, protein, and immunohistochemical analysis. Serum levels of IL-10 were 12-fold greater in the rAAV1–IL-10 group by 4 wk after rAAV1–IL-10 administration (345 ± 169 versus 28 ± 15 pg/ml; P = 0.001), and levels were maintained throughout the experiment. rAAV1–IL-10 treatment resulted in less proteinuria (P < 0.05), lower serum creatinine (P < 0.05), and higher creatinine clearances (P < 0.01) compared with rAAV1-GFP–treated rats. Renal interstitial infiltration was significantly attenuated by rAAV1–IL-10 administration as assessed by numbers of CD4+, CD8+, monocyte-macrophages (ED-1+) and dendritic (OX-62+) cells (P < 0.05), and this correlated with reductions in the renal expression of monocyte (renal monocyte chemoattractant protein-1 mRNA and protein) and T cell (RANTES mRNA) chemokines. rAAV1–IL-10 administration decreased mRNA levels of IFN-
and IL-2 in the kidney. The reduction in inflammatory cells was associated with a significant reduction in glomerulosclerosis and interstitial fibrosis. It is concluded that IL-10 blocks inflammation and improves renal function in this model of chronic renal disease. The feasibility of long-term overexpression of a gene using the AAV serotype 1 vector system in a model of renal disease is also demonstrated.
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