Noncanonical TGF- pathways, mTORC1 and Abl, in renal interstitial fibrogenesis

Wang S, Wilkes MC, Leof EB, Hirschberg R. Noncanonical TGFpathways, mTORC1 and Abl, in renal interstitial fibrogenesis. Am J Physiol Renal Physiol 298: F142–F149, 2010. First published October 21, 2009; doi:10.1152/ajprenal.00320.2009.—Renal interstitial fibrosis is a major determinant of renal failure in the majority of chronic renal diseases. Transforming growth factor(TGF) is the single most important cytokine promoting renal fibrogenesis. Recent in vitro studies identified novel non-smad TGFtargets including p21-activated kinase-2 (PAK2), the abelson nonreceptor tyrosine kinase (c-Abl), and the mammalian target of rapamycin (mTOR) that are activated by TGFin mesenchymal cells, specifically in fibroblasts but less in epithelial cells. In the present studies, we show that non-smad effectors of TGFincluding PAK2, c-Abl, Akt, tuberin (TSC2), and mTOR are activated in experimental unilateral obstructive nephropathy in rats. Treatment with c-Abl or mTOR inhibitors, imatinib mesylate and rapamycin, respectively, each blocks noncanonical (non-smad) TGFpathways in the kidney in vivo and diminishes the number of interstitial fibroblasts and myofibroblasts as well as the interstitial accumulation of extracellular matrix proteins. These findings indicate that noncanonical TGFpathways are activated during the early and rapid renal fibrogenesis of obstructive nephropathy. Moreover, the current findings suggest that combined inhibition of key regulators of these non-smad TGFpathways even in dose-sparing protocols are effective treatments in renal fibrogenesis.