FOLLISTATIN MODULATES ISCHAEMIA-REPERFUSION-INDUCED RENAL FIBROSIS IN MICE

D FANG1,2, B LU1, S HAYWARD3 D DE KRETSER3,4, P COWAN1,2, K DWYER2

1Immunology Research Centre, St. Vincent’s Hospital Melbourne, Victoria; 2Department of Medicine, the University of Melbourne, Victoria; 3Hudson Institute of Medical Research, Victoria; 4Monash University, Clayton, Victoria

Aim: To examine the therapeutic potential of follistatin in renal fibrosis.

Background: Activin and its binding protein, follistatin, play critical roles in the regulation of inflammation and fibrosis. Activins are upregulated in ischaemia-reperfusion injury (IRI). Injection of a viral vector carrying the follistatin gene (rAAV-FS) results in sustained elevation of circulating follistatin in mice and attenuates ischaemia-reperfusion-induced acute kidney injury.

Methods: 2 groups of mice underwent renal IRI surgery. Group 1 had rAAV-FS or empty-vector (control) injected 4 weeks before IRI (to ensure elevated follistatin levels at the time of injury). Group 2 had the vectors injected immediately before IRI (i.e. normal follistatin levels at the time of injury, but increasing thereafter). Mice were sacrificed 4 weeks post-reperfusion. Serum activin, follistatin and creatinine, Masson’s stained kidney sections and pro-fibrotic markers were assessed.

Results: Four weeks post-IRI, control mice had increased expression of pro-fibrotic markers (TGFβ-1, p<0.01; connective tissue growth factor (CTGF), p<0.05; collagen I, p<0.01; collagen IV, p<0.01), renal fibrosis (p<0.01), and serum creatinine (p<0.01). Compared to control mice, rAAV-FS treated IRI mice had 6-fold increase in circulating follistatin levels (p<0.0001) with associated reductions in activin A and B (p<0.001). rAAV-FS treated IRI mice in group 1 had significant reduction in expression of pro-fibrotic markers (TGFβ-1, p<0.05; CTGF, p<0.05; collagen I, p<0.01; collagen IV, p=0.05), renal fibrosis (p<0.01), and serum creatinine (p<0.05). However, rAAV-FS treated IRI mice in group 2 did not have statistically significant reduction in pro-fibrotic markers, renal fibrosis (p=0.06) and serum creatinine.

Conclusions: Elevated follistatin around IRI seems crucial to protect against renal fibrosis development. These data suggest early post-IRI may be the key period that follistatin acts to modulate renal fibrosis.

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