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

Abstract

Transforming growth factor-beta (TGF-beta) is the single most important cytokine promoting renal fibrogenesis. p21-activated kinase-2 (PAK2) and activation of abelson nonreceptor tyrosine kinase (c-abl) have been shown recently to be smad-independent, fibroblast-specific targets downstream of the activated TGF-beta receptor. In the current study we show that in cultured NRK49F-renal fibroblasts (but not in tubular or mesangial cells) TGF-beta 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-beta addition without affecting PAK2. These in vitro findings were extended to rats with unilateral obstructive nephropathy, a disease model of TGF-beta-driven renal fibrogenesis. In obstructed kidneys, PAK2 and c-abl activity were increased but only c-abl activation was blocked by imatinib. Treatment with imatinib did not prevent renal interstitial infiltration of macrophages or phosphorylation and nuclear translocation of smad2/3 in obstructed kidneys. In contrast, imatinib substantially inhibited an increase in the number of interstitial fibroblasts and myofibroblasts and reduced the expression and interstitial accumulation of collagen type III, collagen type IV and fibronectin. These findings indicate that TGF-beta-induced activation of the nonreceptor c-abl tyrosine kinase regulates fibroblast proliferation and, by this means, is a costimulatory signal in TGF-beta-dependent renal fibrogenesis. Inhibition of c-abl activity with imatinib mesylate ameliorates experimental renal fibrosis in rats.

Imatinib mesylate reduces production of extracellular matrix and prevents development of experimental dermal fibrosis

“…Indeed, consistent with the data presented herein, imatinib mesylate has been shown to reduce the accumulation of ECM proteins in a model of pulmonary fibrosis. In addition, it reduced renal ECM accumulation in a model of unilateral obstructive nephropathy (11)(12)(13).…”

“…Imatinib mesylate is a small-molecule tyrosine kinase inhibitor that binds to the ATP-binding pocket of c-Abl and efficiently blocks its tyrosine kinase activity. Notably, c-Abl has recently been identified as an important downstream molecule in TGF␤ signaling (11)(12)(13). Using mouse embryonic fibroblasts deficient in c-Abl, Daniels et al demonstrated that c-Abl is crucial for the induction of ECM proteins by TGF␤ and that inhibition of c-Abl by imatinib mesylate reduced the synthesis of ECM components in vitro and in vivo in a lung fibrosis model (11).…”

The immune system and cardiac repair

“…In contrast, the structurally divergent Smad6 and Smad7 inhibit TGF-β signaling (inhibitory Smads). Recently, it has become increasingly apparent that TGF-β not only activates Smads, but also signals through Smad-independent pathways [321] that may involve c-Abl [322], p21-activated kinase-2 (PAK2) [323], TGF-β Activated Kinase (TAK)-1 [324], and p38 MAPK [325].…”

Smad1 pathway is activated in systemic sclerosis fibroblasts and is targeted by imatinib mesylate

“…With respect to fibrosis, the nonreceptor tyrosine kinase c-Abl is of special interest, because of the potent antifibrotic effects of the pharmacologic inhibitor of c-Abl, imatinib mesylate. Imatinib mesylate has been shown to inhibit profibrotic effects of TGF␤ in cultured cells, including SSc fibroblasts (5), and to prevent lung and kidney fibrosis in experimental mouse models (6,7). TGF␤ activation of c-Abl occurs through phosphatidylinositol 3-kinase and p21-activated kinase 2 and is independent of the Smad2/3 pathway (8).…”