Inhibition of heparanase protects against chronic kidney dysfunction following ischemia/reperfusion injury
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Valentina Masola1,2, Gloria Bellin1,3, Gisella Vischini4, Luigi Dall’Olmo5, Simona Granata1, Giovanni Gambaro1, Antonio Lupo1, Maurizio Onisto2 and Gianluigi Zaza1
1Renal Unit, Department of Medicine, University Hospital of Verona, Verona, Italy
2University of Padova, Department of Biomedical Sciences, Padua, Italy
3Maria Cecilia Hospital, GVM Care and Research, Cotignola, Ravenna, Italy
4Università Cattolica del Sacro Cuore, Rome, Italy
5Azienda Ulss 3 Serenissima-Ospedale San Giovanni e Paolo, Venice, Italy
Maurizio Onisto, email: firstname.lastname@example.org
Keywords: heparanase; fibrosis; chronic kidney disease; inflammation
Received: June 19, 2018 Accepted: October 24, 2018 Published: November 16, 2018
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.
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