Despite the high prevalence of
acute kidney injury (AKI) and its association with increased morbidity and mortality, therapeutic approaches for AKI are disappointing. This is largely attributed to poor understanding of the pathogenesis of AKI.
Heparanase, an
endoglycosidase that cleaves
heparan sulfate, is involved in extracellular matrix turnover,
inflammation, kidney dysfunction, diabetes,
fibrosis, angiogenesis and
cancer progression. The current study examined the involvement of
heparanase in the pathogenesis of ischemic reperfusion (I/R) AKI in a mouse model and the protective effect of PG545, a potent
heparanase inhibitor. I/R induced tubular damage and elevation in serum
creatinine and blood
urea nitrogen to a higher extent in
heparanase over-expressing transgenic mice vs. wild type mice. Moreover, TGF-β,
vimentin,
fibronectin and α-smooth muscle actin,
biomarkers of
fibrosis, and TNFα,
IL6 and
endothelin-1,
biomarkers of
inflammation, were upregulated in I/R induced AKI, primarily in
heparanase transgenic mice, suggesting an adverse role of
heparanase in the pathogenesis of AKI. Remarkably, pretreatment of mice with PG545 abolished kidney dysfunction and the up-regulation of
heparanase, pro-inflammatory (i.e., IL-6) and pro-fibrotic (i.e., TGF-β) genes induced by I/R. The present study provides new insights into the involvement of
heparanase in the pathogenesis of ischemic AKI.Our results demonstrate that
heparanase plays a deleterious role in the development of renal injury and kidney dysfunction,attesting
heparanase inhibition as a promising therapeutic approach for AKI.