Heparanase mediates renal dysfunction during early sepsis in mice

Abstract

Heparanase, a heparan sulfate-specific glucuronidase, mediates the onset of pulmonary neutrophil adhesion and inflammatory lung injury during early sepsis. We hypothesized that glomerular heparanase is similarly activated during sepsis and contributes to septic acute kidney injury (AKI). We induced polymicrobial sepsis in mice using cecal ligation and puncture (CLP) in the presence or absence of competitive heparanase inhibitors (heparin or nonanticoagulant N-desulfated re-N-acetylated heparin [NAH]). Four hours after surgery, we collected serum and urine for measurement of renal function and systemic inflammation, invasively determined systemic hemodynamics, harvested kidneys for histology/protein/mRNA, and/or measured glomerular filtration by inulin clearance. CLP-treated mice demonstrated early activation of glomerular heparanase with coincident loss of glomerular filtration, as indicated by a >twofold increase in blood urea nitrogen (BUN) and a >50% decrease in inulin clearance (P < 0.05) in comparison to sham mice. Administration of heparanase inhibitors 2 h prior to CLP attenuated sepsis-induced loss of glomerular filtration rate, demonstrating that heparanase activation contributes to early septic renal dysfunction. Glomerular heparanase activation was not associated with renal neutrophil influx or altered vascular permeability, in marked contrast to previously described effects of pulmonary heparanase on neutrophilic lung injury during sepsis. CLP induction of renal inflammatory gene (IL-6, TNF-α, IL-1β) expression was attenuated by NAH pretreatment. While serum inflammatory indices (KC, IL-6, TNF-α, IL-1β) were not impacted by NAH pretreatment, heparanase inhibition attenuated the CLP-induced increase in serum IL-10. These findings demonstrate that glomerular heparanase is active during sepsis and contributes to septic renal dysfunction via mechanisms disparate from heparanase-mediated lung injury.

Heparanase Mediates Intestinal Inflammation and Injury in a Mouse Model of Sepsis

“…In humans, the plasma level and activity of heparanase are elevated in septic shock. 18 Several animal studies indicate that heparanase plays critical roles in sepsis-associated acute pulmonary injury 10 and renal failure, 19 yet its role in septic intestinal injury is unclear. In this study, we investigated the role of heparanase in septic intestinal injury using a mouse sepsis model of cecal ligation and puncture (CLP).…”

Pharmacology of Heparin and Related Drugs

“…Such results suggest that heparanase may well be anti-inflammatory under certain circumstances or in certain tissues. Nonetheless, heparanase was also recently demonstrated to contribute to the renal dysfunction during sepsis in mice (Lygizos et al, 2013). Furthermore, heparanase inhibitors have been demonstrated to prevent the endotoxemia associated loss of the glycocalyx on the vascular endothelium and neutrophil attachment (Schmidt et al, 2012).…”

Urinary Glycosaminoglycans Predict Outcomes in Septic Shock and Acute Respiratory Distress Syndrome

“…Using a mouse model of polymicrobial sepsis, we recently observed septic induction of renal heparanase, a heparan sulfate (HS)-specific endoglucuronidase (7). HS, the most abundant glycocalyx GAG, is a linear sulfated polysaccharide composed of repeating hexuronic acid: glucosamine disaccharides ( Figure 1).…”

“…There is increasing appreciation for the importance of the endothelial glycocalyx to lung (6) and kidney (7,8) homeostasis. The glycocalyx (and its in vivo manifestation, the endothelial surface layer) is a substantial layer of glycosaminoglycans (GAGs) and associated proteoglycans lining the vascular lumen ( Figure 1).…”