Proliferative m-TOR Pathway Is Associated with Injury Tolerance and Repairing in Rat Kidneys
PL Zhang, W Li, RE Brown. William Beaumont Hospital, Royal Oak, MI; University of Texas Health Sciences Center, Houston, TX
Background: Renal injury is known to trigger upregulation of many intracellular signal proteins, but role of mammalian target of rapamycin (m-TOR) prolifeative pathway in injured kidneys remains unknown. In this study, protein expression of phosphorylated (p)-mTOR and its down-stream signal p-p70S6K in renal tubules and glomeruli of rat kidneys after renal ischemia-reperfusion injury was evaluated.
Design: Three groups of male adult rats all had right nephrectomy on the day of surgical produre (n = 7 in each group). The left kidney was untouched in group 1. In group 2, the left renal artery was clamped for 20 minutes, followed by 48 hours of reperfusion. A third group of rats received a bolus intraperitoneal injection of nephrotoxic tunicamycin (0.1 mg/kg) one day before the surgery and then underwent the same surgical procedure as in group 2. Serum creatinine was measured in each rat. The rat kidneys were fixed and stained for phosphorylated (p)-mTOR and its down-stream signal p-p70S6K by immunohistochemical method.
Results: Serum creatinine (mg/dl) was significantly higher in group 3 rats (3.82 0.80) than in group 2 rats (0.70 0.07) and group 1 rats (0.37 0.02). Under normal condition, the glomeruli and distal nephron tubules had prominent cytoplasmic expression of p-mTOR and remarkable nuclear expression of p-p70S6K, whereas all segments of proximal tubules had low expression of both markers. In group 2 and group 3 rats, the expression of both markers in glomeruli, S1 segment of proximal tubules and distal nephron tubules was not affected, subjected to the ischemia-reperfusion injury (regardless of tunicamycin treatment). In group 2, both p-mTOR and p-p70S6K were upregualted dominantly in the S3 segment of proximal tubules, following by S2 segment of proximal tubules. These changes were more prominent in group 3, with an additive nephrotoxicity of tunicamycin and corresponding to the morphologic features of acute tubular injury along the vulnerable renal tubules.
Conclusions: Our data suggest that high baseline expression of p-m-TOR and p-p70S6K in glomeruli and distal nephron tubules may be associated injury resistance. The m-TOR proliferative pathway was activated in the injury-vulnerable segment of renal tubules, implying an important role of this proliferative pathway in the repairing process of renal tubules.
Category: Kidney (does not include tumors)
Tuesday, March 10, 2009 1:00 PM
Poster Session IV # 194, Tuesday Afternoon