Inhibition of heparanase protects against chronic kidney dysfunction following ischemia/reperfusion injury

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.

Non-Anticoagulant Heparins as Heparanase Inhibitors

“…A recent study evidenced that Roneparstat, by inhibiting heparanase, almost restored renal function, plasma creatinine and albuminuria. These results opened the way to further investigations on the potential efficacy of Roneparstat in reducing acute kidney injury and preventing chronic pro-fibrotic damage induced by ischemia/reperfusion injury [161].…”

COVID‐19‐induced endotheliitis: emerging evidence and possible therapeutic strategies

“…Indeed, administration of N‐acetylheparin (NAH) in murine models of sepsis ameliorated lung and intestinal injury and subsequent oedema by reducing tissue neutrophilic infiltration and suppressing IL‐6, IL‐1β and TNF‐α production 110,111 . Furthermore, roneparstat, the most developed glycol‐split NAH, restored pathological renal cellular damage caused by ischaemia‐reperfusion by reducing release of pro‐inflammatory cytokines and reverted established fibrotic processes, thus restoring normal tissue histology in preclinical models 112 . This aspect is especially relevant, considering the extensive formation of fibrosis and irreversible end‐organ damage in post‐BMT syndromes, SCD and advanced COVID‐19.…”

The Endothelial Glycocalyx as a Target of Ischemia and Reperfusion Injury in Kidney Transplantation—Where Have We Gone So Far?

“…Similarly, IRI induces a long-term over-expression of heparanase by the kidneys, following the initial insult, which is compatible with the establishment of chronic allograft nephropathy in kidney transplantation. Gene expression analysis and immunofluorescence staining of kidney tissue from mice with unilaterally induced renal IRI, revealed amplified expression of heparanase in the glomeruli and in the interstitial cells even 8 weeks after the procedure of unilateral renal artery clamping [ 112 ]. This was associated respectively with increased collagen accumulation, up-regulation of MMP-2 and MMP-9, increased TNF-α, IL-1b and IL-6 gene expression as well as higher renal and plasma levels of malondialdehyde, a lipid peroxidation product [ 112 ].…”

“…Gene expression analysis and immunofluorescence staining of kidney tissue from mice with unilaterally induced renal IRI, revealed amplified expression of heparanase in the glomeruli and in the interstitial cells even 8 weeks after the procedure of unilateral renal artery clamping [ 112 ]. This was associated respectively with increased collagen accumulation, up-regulation of MMP-2 and MMP-9, increased TNF-α, IL-1b and IL-6 gene expression as well as higher renal and plasma levels of malondialdehyde, a lipid peroxidation product [ 112 ]. On the other hand, administration of Roneparstat, a heparanase inhibitor, abrogated all the above effects.…”