Abstract
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.
Highlights
Ischemia/reperfusion is defined as a clinicalpathological condition in which an initial limitation of blood supply to an organ occurs, followed by a subsequent phase of perfusion and re-oxygenation
Eight weeks after the operation, gene expression analysis of the total renal parenchyma revealed the significant up-regulation of HPSE in I/R-injured mice while it was significantly reduced by treatment with RONE (Figure 1A)
In I/R mice, we found prominent fibrosis in the interstitial cortex which was significantly reduced by treatment with both RONE doses (Figure 2A and 2B)
Summary
Ischemia/reperfusion is defined as a clinicalpathological condition in which an initial limitation of blood supply to an organ occurs, followed by a subsequent phase of perfusion and re-oxygenation. The subsequent restoration of blood flow and re-oxygenation is very often associated with further tissue lesions and a deep inflammatory response. Strategies have been tested and implemented to avoid or relieve renal I/R, the morbidity and mortality of the ensuing ischemic acute kidney injury (AKI) still remains high [3]. In transplanted patients it is associated with delayed graft function (DGF) and the development of chronic allograft nephropathy (CAN) [3, 4]. In settings other than kidney transplantation, patients who survive AKI can develop, in the long term, chronic kidney disease (CKD) and end-stage renal disease (ESRD)
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