Imatinib mesylate blocks a non‐Smad TGF‐β pathway and reduces renal fibrogenesis in vivo

Abstract

Transforming growth factor‐β (TGF‐β) is the single most important cytokine promoting renal fibrogenesis. p21‐activated kinase‐2 (PAK2) and activa‐ tion of abelson nonreceptor tyrosine kinase (c‐abl) have been shown recently to be smad‐independent, fibro‐ blast‐specific targets downstream of the activated TGF‐β receptor. In the current study we show that in cultured NRK49F‐renal fibroblasts (but not in tubular or mesangial cells) TGF‐β similarly activates PAK2 as well as c‐abl and induces cell proliferation. Inhibition of the c‐abl kinase with imatinib mesylate prevents increased proliferation after TGF‐β addition without affecting PAK2. These in vitro findings were extended to rats with unilateral obstructive nephropathy, a dis‐ ease model of TGF‐β‐driven renal fibrogenesis. In obstructed kidneys, PAK2 and c‐abl activity were in‐ creased but only c‐abl activation was blocked by ima‐ tinib. Treatment with imatinib did not prevent renal interstitial infiltration of macrophages or phosphoryla‐ tion and nuclear translocation of smad2/3 in ob‐ structed kidneys. In contrast, imatinib substantially inhibited an increase in the number of interstitial fibroblasts and myofibroblasts and reduced the expres‐ sion and interstitial accumulation of collagen type III, collagen type IV and fibronectin. These findings indi‐ cate that TGF‐β‐induced activation of the nonreceptor c‐abl tyrosine kinase regulates fibroblast proliferation and, by this means, is a costimulatory signal in TGF‐β‐ dependent renal fibrogenesis. Inhibition of c‐abl activ‐ ity with imatinib mesylate ameliorates experimental renal fibrosis in rats.—Wang, S., Wilkes, M. C., Leof, L. B., Hirschberg, R. Imatinib mesylate blocks a non‐ Smad TGF‐β pathway and reduces renal fibrogenesis in vivo. FASEB J. 19, 1‐11 (2005)