Mesangial cells initiate compensatory renal tubular hypertrophy via IL-10-induced TGF-beta secretion: effect of the immunomodulator AS101 on this process.
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-beta by mesangial cells isolated from the remaining kidneys was increased significantly, compared with those of control and sham animals. Moreover, TGF-beta 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-beta content in plasma and renal tissue. AS101 treatment decreased IL-10 and TGF-beta 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-beta 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-beta production by mesangial cells, thus limiting compensatory tubular cell hypertrophy.
Nephrology Division, Assaf Harofeh Medical Center, 70300 Zerifin, Israel.
Inna
I
Sinuani
Zhan
Z
Averbukh
Inna
I
Gitelman
Micha J
MJ
Rapoport
Judit
J
Sandbank
Michael
M
Albeck
Benjamin
B
Sredni
Joshua
J
Weissgarten
D000818:Animals; D002478:Cells, Cultured; D005030:Ethylenes / Q000494:pharmacology*; D006984:Hypertrophy / Q000473:pathology / Q000503:physiopathology; D007155:Immunologic Factors / Q000494:pharmacology*; D016753:Interleukin-10 / Q000032:analysis / Q000378:metabolism / Q000502:physiology*; D007684:Kidney Tubules / Q000737:chemistry / Q000473:pathology* / Q000503:physiopathology; D008297:Male; D050527:Mesangial Cells / Q000737:chemistry / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016212:Transforming Growth Factor beta / Q000032:analysis / Q000378:metabolism* / Q000502:physiology
D005030:Ethylenes; D007155:Immunologic Factors; D016212:Transforming Growth Factor beta; D016753:Interleukin-10; C054105:ammonium trichloro(dioxoethylene-O,O'-)tellurate