Renal
ischemia/reperfusion (I/R) injury occurs in patients undergoing
renal transplantation and with
acute kidney injury and is responsible for the development of chronic allograft dysfunction as characterized by parenchymal alteration and
fibrosis.
Heparanase (HPSE), an
endoglycosidase that regulates EMT and macrophage polarization, is an active player in the biological response triggered by
ischemia/reperfusion (I/R) injury. I/R was induced in vivo by clamping left renal artery for 30 min in wt C57BL/6J mice. Animals were daily treated and untreated with
Roneparstat (an inhibitor of HPSE) and sacrificed after 8 weeks. HPSE,
fibrosis, EMT-markers,
inflammation and oxidative stress were evaluated by biomolecular and histological methodologies together with the evaluation of renal histology and measurement of renal function parameters. 8 weeks after I/R HPSE was upregulated both in renal parenchyma and plasma and tissue specimens showed clear evidence of renal injury and
fibrosis. The inhibition of HPSE with
Roneparstat-restored histology and
fibrosis level comparable with that of control. I/R-injured mice showed a significant increase of EMT,
inflammation and oxidative stress markers but they were significantly reduced by treatment with
Roneparstat. Finally, the inhibition of HPSE in vivo almost restored renal function as measured by BUN, plasma
creatinine and
albuminuria. The present study points out that HPSE is actively involved in the mechanisms that regulate the development of renal
fibrosis arising in the transplanted organ as a consequence of
ischemia/
reperfusion damage. HPSE inhibition would therefore constitute a new pharmacological strategy to reduce
acute kidney injury and to prevent the chronic pro-fibrotic damage induced by I/R.