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Secretion: Effect of the Immunomodulator AS101 on this process
1 Nephrology, Nephrology division , Assaf Harofeh Medical Center, Zerifin, Israel; C.A.I.R. Institute, Faculty of Life Sciencies , Bar Ilan University, Ramat Gan, Israel
2 Nephrology, Nephrology division , Assaf Harofeh Medical Center, Zerifin, Israel
3 Molecular Genetics of Development, Ben Gurion University, Beer Sheva, Israel
4 Medicine C, Assaf Harofeh Medical Center, Zerifin, Israel
5 Pathology, Assaf Harofeh Medical Center, Zerifin, Israel
6 Chemistry, Faculty of Exact Sciences, Bar Ilan University, Ramat Gan, Israel
7 C.A.I.R. Institute, Faculty of Life Sciencies , Bar Ilan University, Ramat Gan, Israel
* To whom correspondence should be addressed. E-mail: averbukhzh{at}asaf.health.gov.il.
The present study investigated the role of IL-10 produced by the mesangial cells in postnephrectomy compensatory renal growth and the effect of the immunomodulator AS101 on this process.
140 unilateral nephrectomized and sham operated male Sprague Dawley rats were treated by AS101 or PBS before and after surgery. The results show that secretion of IL-10 and TGF-
by mesangial cells isolated from the remaining kidneys were increased significantly, compared to those of control and sham animals. Moreover, TGF- secretion by mesangial cells was increased after the addition of exogenous recombinant IL-10 and inhibited in the presence of neutralizing anti IL-10 antibodies. In vivo, compensatory growth of the remaining kidneys was associated with significant increase in IL-10 content in renal tissues and plasma. Immunohistochemical studies show that IL-10 was produced by mesangial cells. Elevated IL-10 levels were followed by the rise in TGF- content in plasma and renal tissue. AS101 treatment decreased IL-10 and TGF- expression in plasma and kidney tissues and results in 25% reduction in the fresh and fractional kidney weight, and decreased hypertrophy of tubular cells (protein/DNA ratio, morphometric analysis).
Taken together, these data demonstrate that TGF- production by mesangial cells is IL-10 dependent. Mesangial cells are the major source of IL-10 in kidneys. AS101, by inhibiting the activity of IL-10, decreases TGF- production by mesangial cells, thus limiting compensatory tubular cell hypertrophy.
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