Progression of renal disease in interleukin‐4 transgenic mice: involvement of transforming growth factor‐β

Abstract

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.

B cell–derived IL-4 acts on podocytes to induce proteinuria and foot process effacement

“…IL-4 is secreted by Th2 helper T cells and associated with atopy, a condition that is highly associated with MCD (64,65). Transgenic mice expressing IL-4 develop glomerulosclerosis (53,(66)(67)(68) and transgenic rats expressing IL-13 develop proteinuria (69). While it was reported previously that podocytes express the IL-4 receptor (IL-4Rα and common γ-chain) and can respond to IL-4 (23), attempts to link IL-4 levels in serum and urine with nephrotic diseases have been largely unrevealing (70,71).…”

A Novel In Vitro Human Model of Hemangioma

“…RNA was reverse transcribed to cDNA and amplified using the Perkin Elmer (Norwalk, CT) rTth RT-PCR kit as described (17)(18)(19)(20)(21). Briefly, a 10-min RT step was followed by 40 cycles of three-stage PCR using temperatures of 94°C for denaturing, 72°C for extension, and specific annealing temperatures for each primer set ( Table 3).…”

Interleukin-4 transgenic mice develop glomerulosclerosis independent of immunoglobulin deposition

“…1 C). Glomeruli within each kidney showed a similar degree of scarring as observed in the kidneys of IL-4 tg mice [9], while none of the glomeruli were sclerosed in the wt/ ? MT -/and wt/ ?…”

“…By 3 weeks of age, all IL-4 tg mice develop glomerulosclerosis with Ig and complement deposition, suggesting that the renal lesions are immune-mediated [8]. However, 1-week-old IL-4 tg mice show early glomerular fibrotic changes despite the absence of immune deposits [9]. Here we have addressed questions aimed at elucidating the etiology of the glomerulosclerotic lesions in this model concentrating on the role of glomerular immune deposition and the effect of renal IL-4 expression in the development of disease.…”

“…There was no statistical difference in the GSI between IL-4 tg mice and IL- Progressive glomerulosclerosis in IL-4 tg/ ? MT -/mice led to severe oliguria similar to that seen in IL-4 tg animals [9]. Therefore, we were unable to determine proteinuria as a measure of renal failure.…”