IL-10 suppresses chemokines, inflammation, and fibrosis in a model of chronic renal disease.
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-gamma 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.
Mu
Wei
W
Division of Nephrology, Powell Gene Therapy Center, University of Florida, Gainesville, FL 32610, USA.
Ouyang
Xiaosen
X
Agarwal
Anupam
A
Zhang
Li
L
Long
David A
DA
Cruz
Pedro E
PE
Roncal
Carlos A
CA
Glushakova
Olena Y
OY
Chiodo
Vince A
VA
Atkinson
Mark A
MA
Hauswirth
William W
WW
Flotte
Terry R
TR
Rodriguez-Iturbe
Bernardo
B
Johnson
Richard J
RJ
D000818:Animals; D001707:Biopsy, Needle; D018925:Chemokines / Q000378:metabolism*; D016207:Cytokines / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D005355:Fibrosis / Q000188:drug therapy / Q000473:pathology; D005786:Gene Expression Regulation; D007150:Immunohistochemistry; D016753:Interleukin-10 / Q000097:blood* / Q000494:pharmacology*; D007676:Kidney Failure, Chronic / Q000188:drug therapy* / Q000473:pathology*; D007677:Kidney Function Tests; D008297:Male; D009395:Nephritis, Interstitial / Q000473:pathology* / Q000503:physiopathology; D011507:Proteinuria / Q000503:physiopathology; D012333:RNA, Messenger / Q000032:analysis / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D012016:Reference Values; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012680:Sensitivity and Specificity
D018925:Chemokines; D016207:Cytokines; D012333:RNA, Messenger; D016753:Interleukin-10