Beneficial Effects of Exogenous Thymosin β4 on Late Stage Tubulointerstitial Fibrosis
Yiqin Zuo, Bongkwon Chun, Hai-Chun Yang, Li-jun Ma, Agnes B Fogo. Vanderbilt University, Nashville, TN
Background: Previously we 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 generated by prolyl oligopeptidase (POP), has anti-fibrotic effects. Moreover, we found that inhibition of POP increased Tβ4 levels, decreased Ac-SDKP levels, and exacerbated the early stage of fibrosis in obstructed kidneys. We have now investigated the long-term effects of thymosin β4 on fibrosis.
Design: Male C57BL/6 mice underwent UUO with treatments as follows, and were sacrificed at day 14: UUO without treatment, UUO+Tβ4 (150µg, i.p. q 3 d), UUO+combination (POP inhibitor, S17092, 40mg/kg/d, by gavage and Tβ4), and UUO+Ac-SDKP (1.6 mg/kg/d, delivered by minipump).
Results: Tubulointerstitial fibrosis assessed by Sirius red morphometric analysis was significantly higher in mice treated with POP inhibitor+Tβ4 combination compared to untreated UUO (3.37±0.21 vs. 2.92±0.09%, p <0.05). Fibrosis was dramatically reduced by Ac-SDKP, and surprisingly, also by Tβ4 alone (Ac-SDKP 2.56±0.13; Tβ4 1.90±0.04%, both p<0.05 vs. untreated). We next examined POP enzyme activity and Ac-SDKP levels in the obstructed kidneys. POP activity was significantly decreased in the UUO kidneys of mice with combination treatment compared to untreated UUO kidneys (29% of levels in untreated UUO, p<0.05). Neither Ac-SDKP nor Tβ4 administration changed POP activity. Ac-SDKP concentration was significantly reduced by combination treatment, but was dramatically increased by Ac-SDKP or Tβ4 administration vs. untreated UUO (combination, 51%; Ac-SDKP, 199%; Tβ4, 149% of untreated UUO, all p<0.05 in treated vs. untreated).
Conclusions: Our study suggests that long-term exogenous Tβ4 administration may have net anti-fibrotic effects in UUO kidneys. The data demonstrate that this beneficial effect could be due to the combined actions of Tβ4 and its downstream product, Ac-SDKP. The potential beneficial effects of Tβ4 need further investigation.
Category: Kidney (does not include tumors)
Tuesday, March 20, 2012 11:00 AM
Platform Session: Section H, Tuesday Morning