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. 2009 Oct 21;298(1):F142–F149. doi: 10.1152/ajprenal.00320.2009

Fig. 2.

Fig. 2.

A: non-smad TGF-β targets p21-activated kinase-2 (PAK2) and c-Abl are activated in obstructive nephropathy. Kinase activity and levels of PAK2 and c-Abl in the right (nonobstructed) and the contralateral (obstructed) kidney were determined as described previously (17) and under materials and methods. Groups consisted of vehicle (control), imatinib (IM or I), rapamycin (Rapa or R), or I + R at the indicated drug concentrations (mg/kg). In obstructive nephropathy, both PAK2 and c-Abl are activated and PAK2 activation is not affected by any of the treatment regimens. At the higher dose (50 mg/kg), imatinib (IM) blocks Abl activation. At the lesser dose of 25 mg/kg, IM inhibition of Abl activity by imatinib is submaximal. B: quantitative assessment of Abl activity in right, control kidneys (open bars) and left, obstructed kidneys (gray bars); n = 3 each. *P < 0.05 vs. control kidneys. **P < 0.05 vs. obstructed kidneys in vehicle-treated rats. C: Akt phosphorylation and mammalian target of rapamycin (mTOR) signaling are induced in obstructive nephropathy. Akt phosphorylation is substantially increased in the obstructed kidney and, as expected, is not modified by treatment with imatinib or rapamycin. Similarly, TSC2 (a substrate of Akt and an inhibitor of mTORC1 which is inactivated by phosphorylation) is phosphorylated to a similar degree in unilateral ureteral obstruction (UUO) rats irrespective of treatment with imatinib (IM or I) or rapamycin (Rapa or R). In contrast, P70S6K, a downstream effector of mTORC1, is activated in obstructive nephropathy and not affected by IM, but very effectively reduced by Rapa even at the lower dose. Thus, mTORC1 is activated during obstructive nephropathy, presumably through TGF-β, and its activation is blocked by Rapa, 1.5 or 0.5 mg/kg. D: quantitative assessment of mTOR activity which was measured as the ratio of phosphorylated over total P70S6K in right, control kidneys (open bars) and left, obstructed kidneys (gray bars); n = 3 each. *P < 0.05 vs. control kidneys. **P < 0.05 vs. obstructed kidneys in vehicle-treated rats.

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