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Mesangial cells initiate compensatory renal tubular hypertrophy via IL-10-induced TGF- secretion: effect of the immunomodulator AS101 on this process

¹Nephrology Division, Assaf Harofeh Medical Center, Zerifin; ²C.A.I.R. Institute, Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan; ³Department of Molecular Genetics of Development, Ben Gurion University, Beer Sheva; ⁴Department of Internal Medicine C, Assaf Harofeh Medical Center, Zerifin; ⁵Department of Pathology, Assaf Harofeh Medical Center, Zerifin; and ⁶Department of Chemistry, Faculty of Exact Sciences, Bar-Ilan University, Ramat Gan, Israel

Submitted 23 October 2005 ; accepted in final form 8 March 2006

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. One hundred forty 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 was increased significantly, compared with 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.

unilateral nephrectomy; cytokines; tubular cells

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