The Role of Activin A and B and the Benefit of Follistatin Treatment in Renal Ischemia-Reperfusion Injury in Mice.
BACKGROUND
Activins, members of the TGF-β superfamily, are key drivers of inflammation and are thought to play a significant role in ischemia-reperfusion injury (IRI), a process inherent to renal transplantation that negatively impacts early and late allograft function. Follistatin (FS) is a protein that binds activin and inhibits its activity. This study examined the response of activin A and B in mice after renal IRI and the effect of exogenous FS in modulating the severity of renal injury.


METHODS
Mice were treated with recombinant FS288 or vehicle before renal IRI surgery. Activin A, B, and FS levels in the serum and kidney, and renal injury parameters were measured at 3, 6, and 24 hours after reperfusion.


RESULTS
Serum and kidney activin B levels were increased within 6 hours postrenal IRI, accompanied by renal injury-increased serum creatinine, messenger (m)RNA expression of kidney injury molecule-1 (KIM-1) and neutrophil gelatinase-associated lipocalin (NGAL); endothelial activation-increased E-selectin mRNA; and systemic inflammation-increased serum levels of IL-6, monocyte chemotactic protein-1 and TNF-α. Further injury was potentiated by an upsurge in activin A by 24 hours, with further increases in serum creatinine, KIM-1 and NGAL mRNA expression. Follistatin treatment significantly reduced the level of serum activin B and subsequently blunted the increase in activin A. Renoprotection was evident with the attenuated rise in serum creatinine, KIM-1 and NGAL expression, tubular injury score, renal cell apoptosis, and serum IL-6 and monocyte chemotactic protein-1 levels.


CONCLUSIONS
We propose that activin B initiates and activin A potentiates renal injury after IRI. Follistatin treatment, through binding and neutralizing the actions of activin B and subsequently activin A, reduced renal IRI by minimizing endothelial cell activation and dampening the systemic inflammatory response. These data support the potential clinical application of FS treatment to limit IRI during renal transplantation.
Immunology Research Centre, St. Vincent's Hospital Melbourne, Victoria, Australia.; Department of Medicine, the University of Melbourne, Victoria, Australia.
Doreen Y P
DY
Fang
Immunology Research Centre, St. Vincent's Hospital Melbourne, Victoria, Australia.
Bo
B
Lu
Hudson Institute of Medical Research, Victoria, Australia.
Susan
S
Hayward
Hudson Institute of Medical Research, Victoria, Australia.; Monash University, Clayton, Victoria, Australia.
David M
DM
de Kretser
Immunology Research Centre, St. Vincent's Hospital Melbourne, Victoria, Australia.; Department of Medicine, the University of Melbourne, Victoria, Australia.
Peter J
PJ
Cowan
Immunology Research Centre, St. Vincent's Hospital Melbourne, Victoria, Australia.; Department of Medicine, the University of Melbourne, Victoria, Australia.
Karen M
KM
Dwyer