The Balance of Thymosin β4 and Its Metabolite Ac-SDKP Modulates Activity of Profibrotic Factors
Y Zuo, SA Potthoff, H-C Yang, L-J Ma, AB Fogo. Vanderbilt University, Nashville, TN
Background: We have previously shown that the G-actin sequestering protein thymosin β4 (Tβ4) is dramatically upregulated in the obstructed kidney in the unilateral ureteral obstruction (UUO) model of tubulointerstitial fibrosis. Tβ4, which is postulated to have profibrotic effects, is degraded by prolyl oligopeptidase (POP) to Ac-SDKP, a peptide with anti-fibrotic actions. Our previous study further revealed that inhibition of POP altered the balance of Tβ4 and Ac-SDKP and exacerbated fibrosis in obstructed kidneys. We now investigated whether the balance of Tβ4 vs Ac-SDKP also affects kidneys without injury.
Design: Adult male C57BL/6 wild type mice underwent UUO and were divided into five groups: 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, starting 5 days before the surgery). Mice were sacrificed 5 days after UUO and the contralateral non-injured kidneys were studied.
Results: POP activity was significantly lower in the contralateral kidneys of mice treated with POP inhibitor, combination or Ac-SDKP (POP inhibitor, 12.7±1.3; combination, 18.3±1.4; Ac-SDKP 25.4±2.6; vs untreated UUO, 40.1±3.0 pmol/min*mg tissue, all p<0.05). The Ac-SDKP level in the contralateral kidneys was remarkably increased only in the group receiving Ac-SDKP (Ac-SDKP, 4.06±0.34; untreated UUO, 2.14±0.30 pmol/mg tissue, p<0.05). Compared to untreated UUO, plasminogen activator inhibitor (PAI-1) and Tβ4 expression in the contralateral kidneys assessed by real time PCR were dramatically reduced by Ac-SDKP treatment, but not affected by POP inhibitor with or without Tβ4. There was no difference in transforming growth factor (TGF)-β1 mRNA among these five groups.
Conclusions: Our study suggests that exogenous Ac-SDKP may have negative feedback to decrease POP enzyme activity, thus potentially decreasing endogenous Ac-SDKP production. However, in the non-injured contralateral kidney, exogenous administration of Ac-SDKP inhibits profibrotic factors. We propose that Ac-SDKP is a crucial molecule in determining fibrosis.
Category: Kidney (does not include tumors)
Wednesday, March 24, 2010 1:00 PM
Poster Session VI # 251, Wednesday Afternoon