Progression of renal disease in interleukin-4 transgenic mice: involvement of transforming growth factor-beta.
Recent reports have suggested the involvement of interleukin-4 (IL-4) in glomerular pathophysiology. Using immunohistochemistry and reverse transcriptase polymerase chain reaction we investigated the renal lesions in transgenic (tg) mice with widely distributed IL-4 expression including the kidney, and measured the serum levels of the cytokines transforming growth factor-beta (TGF-beta) and IL-4 by ELISA. Transgenic animals exhibited glomerular hypertrophy with progressive mesangial sclerosis leading to renal failure. Renal IL-4 transcript expression, mesangial accumulation of collagen types I, III, IV and V, and immune deposition accompanied by increased expression of TGF-beta1 protein and mRNA were observed. Seven day-old transgenic animals showed early renal fibrotic changes in the absence of immune deposits or TGF-beta1 upregulation. The sera of transgenic mice not only showed elevated levels of circulating IL-4 (tg: 76.6 pg/ml +/- 7.1 vs wildtype (wt): < 3 pg/ml), but significantly decreased TGF-beta1 levels (tg: 18.9 ng/ml +/- 4.1 vs wt: 38.7 ng/ml +/- 2.9; P < 0.005). The disease severity correlated with the serum IL-4/TGF-beta1 ratio rather than with the IL-4 concentration. These data suggest that renal IL-4 production results in matrix accumulation prior to any immunological insult, that increased circulating IL-4/TGF-beta1 ratios are associated with renal immunopathological manifestations and that upregulation of renal TGF-beta1 expression following glomerular Ig deposition accelerates the sclerosis and exacerbates disease development.
Rüger
B M
BM
Renal Research Unit, Department of Medicine, Wellington School of Medicine, Wellington, New Zealand. beate@wnmeds.ac.nz
Hasan
Q
Q
Erb
K J
KJ
Davis
P F
PF
D000818:Animals; D018450:Disease Progression; D005921:Glomerulonephritis / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D007124:Immunoenzyme Techniques; D015847:Interleukin-4 / Q000378:metabolism*; D007676:Kidney Failure, Chronic / Q000276:immunology; D051379:Mice; D008822:Mice, Transgenic; D016133:Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D015854:Up-Regulation
D016212:Transforming Growth Factor beta; D015847:Interleukin-4