Altered Balance of Thymosin 4 and Ac-SDKP Exacerbates Tubulointerstitial Fibrosis
Y Zuo, SA Potthoff, TJ Brolin, T Myohanen, N-E Rhaleb, OA Carretero, H-C Yang, L-J Ma, AB Fogo. Vanderbilt University, Nashville, TN; University of Kuopio, Kuopio, Finland; Henry Ford Hospital, Detroit, MI
Background: Our previous study showed that the G-actin sequestering protein thymosin 4 (T4) is remarkably upregulated in the unilateral ureteral obstruction (UUO) model of tubulointerstitial fibrosis. T4 is postulated to be profibrotic but is also degraded by prolyl oligopeptidase (POP) to the anti-fibrotic Ac-SDKP peptide. In this study we investigate whether POP inhibition with or without exogenous T4 affects the early stage of tubulointerstitial fibrosis.
Design: Adult male C57BL/6 wild type mice underwent UUO and were divided into four groups and sacrificed on day 5. Groups were as follows: control UUO without treatment, or with POP inhibitor (S17092, 40mg/kg per day, by gavage), T4 (150g/d, i.p.), or combination treatment (POP inhibitor plus T4).
Results: Tubulointerstitial injury score was dramatically higher in POP inhibitor and combination treatment groups than untreated UUO (POP inhibitor, 2.870.09; combination, 2.940.23; control UUO, 2.220.19, both p<0.05 vs control). POP activity was significantly lower in POP inhibitor and combination groups (POP inhibitor, 2.060.26; combination, 5.731.59; control UUO, 26.622.74 pmol/min*mg tissue, both p<0.05 vs control). Compared to untreated UUO control group, neither injury score nor POP activity was different in T4 group (2.190.13 and 21.191.61 pmol/min*mg tissue, respectively). There was no difference in T4 expression among all four groups by western blot analysis (POP inhibitor, 1.150.17; combination, 0.840.09; control UUO, 1.020.05; T4, 0.830.06). However, the balance of T4 vs Ac-SDKP level in both serum and tissue could be shifted.
Conclusions: Our study suggests that POP inhibitor with or without T4 may cause tubulointerstitial fibrosis by inhibiting degradation of T4 and thus also Ac-SDKP formation. We propose that the balance of T4 and Ac-SDKP may play a pivotal role in determining renal interstitial fibrosis.
Category: Kidney (does not include tumors)
Monday, March 9, 2009 8:45 AM
Platform Session: Section G 1, Monday Morning