Renal interstitial fibrosis is a major determinant of renal failure in the majority of chronic renal diseases. Transforming growth factor beta (TGF) is the single most important cytokine promoting renal fibrogenesis. Recent in-vitro studies have identified novel non-smad TGF targets including p21-activated kinase-2 (PAK2), the abelson non-receptor tyrosine kinase (c-Abl) and the mammalian target of rapamycin (mTOR) that are activated by TGF in mesenchymal cells, specifically in fibroblasts but less in epithelial cells. In the present studies we show that non-smad effectors of TGF including 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 non-canonical (non-smad) TGF pathways 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 non-canonical TGF pathways 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 TGF pathways even in dose-sparing protocols are effective treatments in renal fibrogenesis.