Exogenous Ac-SDKP Administration Regulates Profibrotic Molecules in Obstructed Kidneys.
Yiqin Zuo, Sebastian A Potthoff, Hai-Chun Yang, Li-Jun Ma, Agnes B Fogo. Vanderbilt University, Nashville, TN
Background: Our previous studies showed that thymosin β4 (Tβ4), a G-actin sequestering protein, is remarkably increased in the obstructed kidney in the unilateral ureteral obstruction (UUO) model of tubulointerstitial fibrosis. Ac-SDKP, the degradation product of Tβ4 by prolyl oligopeptidase (POP), is postulated to have anti-fibrotic effects. Moreover, we found that inhibition of POP shifted the balance of Tβ4 and Ac-SDKP and exacerbated fibrosis in obstructed kidneys. We have now investigated profibrotic molecular gene expression in the UUO kidneys.
Design: Male C57BL/6 mice were sacrificed at day 5 after UUO and treatments: UUO without treatment, UUO+POP inhibitor (S17092, 40mg/kg per day, by gavage), UUO+Tβ4 (150µg/d, i.p.), UUO+combination (POP inhibitor and Tβ4), and UUO+Ac-SDKP (1.6 mg/kg/d, delivered by minipump).
Results: POP activity was significantly decreased in the obstructed kidneys of mice treated with either POP inhibitor or the combination (8% and 21% of levels in untreated UUO, respectively, both p<0.05). Ac-SDKP concentration was significantly reduced by both the POP inhibitor and combination treatment but dramatically increased by Ac-SDKP administration vs. untreated UUO (POP inhibitor, 47%; combination, 61%; Ac-SDKP, 172% of untreated UUO, respectively, all p<0.05). Neither POP activity nor Ac-SDKP was affected by Tβ4 treatment (77% and 78% of untreated UUO, respectively). Ac-SDKP treatment dramatically decreased plasminogen activator inhibitor (PAI-1), transforming growth factor (TGF)-β1, Tβ4, collagen I and III expression assessed by real time PCR vs. untreated UUO. By contrast, PAI-1, TGF-β1 and collagen III expressions were significantly increased by POP inhibitor. Ku80, a potential receptor for Tβ4, was abundantly present in glomerular endothelial cells and peritubular capillary endothelium in UUO kidneys and increased vs. non-obstructed kidneys. Ku80 mRNA in the UUO kidney assessed by real time PCR was dramatically increased by POP inhibitor and Tβ4 treatment vs. untreated UUO.
Conclusions: Our study suggests that exogenous administration of Ac-SDKP inhibits profibrotic factors. We propose that the balance of thymosin β4 and Ac-SDKP is crucial in determining tubulointerstitial fibrosis, and Ku80, a potential receptor for Tβ4, may modulate these processes.
Category: Kidney (does not include tumors)
Wednesday, March 2, 2011 1:00 PM
Poster Session VI # 259, Wednesday Afternoon