Abstract
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.
Highlights
Acute kidney injury (AKI) is a common clinical disorder affecting 2-7% of hospitalized patients and some 20-50% of critically ill subjects [1, 2]
We have previously reported that heparanase is involved in the onset and development of ischemic reperfusion (I/R)-induced epithelial to mesenchymal transition (EMT) both in vitro and in vivo [35] and Lygizos et al [36] found that glomerular heparanase is activated during sepsis and contributes to septic AKI
Immunofluorescence www.impactjournals.com/oncotarget staining of renal tissue of wt animals confirmed that acute ischemic renal injury up-regulated heparanase in glomeruli, tubular cells and interstitial cells (Figure 1B)
Summary
Acute kidney injury (AKI) is a common clinical disorder affecting 2-7% of hospitalized patients and some 20-50% of critically ill subjects [1, 2]. Toxic insult and sepsis are the leading causes of clinical AKI [1, 2]. AKI is characterized by decreased oxygen delivery, depletion of cellular energy stores and accumulation of toxic metabolites. The cellular depletion of ATP, a hallmark of ischemic injury, leads to a series of morphological, biochemical and physiological derangements [2,3,4]. Reperfusion of ischemic tissue, necessary for repair, has been shown to exacerbate AKI owing to the generation of reactive oxygen and nitrogen species [2,3,4,5,6]. Despite the advances in critical care medicine, AKI is still associated with high morbidity and mortality assumedly due to delayed detection of the disease and lack of effective treatment [7]
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