Protective Effects of Recombinant Human Soluble Thrombomodulin on Lipopolysaccharide-Induced Acute Kidney Injury

Abstract

Thrombomodulin (TM) is a single transmembrane, multidomain glycoprotein receptor for thrombin, and is best known for its role as a cofactor in a clinically important natural anticoagulant pathway. In addition to its anticoagulant function, TM has well-defined anti-inflammatory properties. Soluble TM levels increase significantly in the plasma of septic patients; however, the possible involvement of recombinant human soluble TM (rTM) transduction in the pathogenesis of lipopolysaccharide (LPS)-induced nephrotoxicity, including acute kidney injury (AKI), has remained unclear. Mice were injected intraperitoneally with 15 mg/kg LPS. rTM (3 mg/kg) or saline was administered to the animals before the 3 and 24 h LPS-injection. At 24 and 48 h, blood urea nitrogen, the inflammatory cytokines in sera and kidney, and histological findings were assessed. Cell activation and apoptosis signal was assessed by Western blot analysis. In this study using a mouse model of LPS-induced AKI, we found that rTM attenuated renal damage by reducing both cytokine and cell activation and apoptosis signals with the accumulation of CD4+ T-cells, CD11c+ cells, and F4/80+ cells via phospho c-Jun activations and Bax expression. These findings suggest that the mechanism underlying these effects of TM may be mediated by a reduction in inflammatory cytokine production in response to LPS. These molecules might thereby provide a new therapeutic strategy in the context of AKI with sepsis.

Renal microvascular endothelial cell responses in sepsis-induced acute kidney injury

“…Antithrombotic activity is regulated by endothelial thrombomodulin (TM), which binds to thrombin and thereby prevents its interaction with platelets and coagulation factors. TM also mediates activation of protein C, which in turn degrades coagulation factors and creates an anti-inflammatory and barrier-stabilizing status of endothelial cells via endothelial protein C receptor (EPCR) and protease-activated receptor 1 (PAR1) 23,24 .…”

Protective Role of Recombinant Human Thrombomodulin in Diabetes Mellitus

“…In the current study, we evaluated the potential of rhTM as an antiapoptotic drug in DM on the basis of evidence showing its strong anti-apoptotic activity in several organ injury models. Treatment with rhTM inhibited cell apoptosis in experimental animal models of lipopolysaccharide-induced acute kidney injury, hepatic ischemia-reperfusion injury, hepatic sinusoidal obstruction syndrome, cardiopulmonary-bypass-induced acute lung injury, ischemic myocardial injury, atherosclerosis, diabetic nephropathy, glomerulosclerosis, and pulmonary fibrosis [ 18 , 21 , 22 , 23 , 24 , 36 , 37 , 38 , 39 , 40 ]. In vitro experiments have shown that rhTM suppresses the apoptosis of endothelial cells, alveolar epithelial cells, hepatocytes, hepatic sinusoidal cells, and podocytes [ 24 , 36 , 38 , 39 , 40 ].…”

“…TM has preventive effects in diabetic renopathy and ischemia–reperfusion renal injury [ 18 , 19 , 20 ]. Treatment with a recombinant human TM (rhTM) containing the three extracellular domains of the protein ameliorates acute kidney injury, hemolytic uremic syndrome, chronic kidney fibrosis with renal failure, pulmonary fibrosis, and allergic bronchial asthma in experimental mouse disease models [ 14 , 21 , 22 , 23 , 24 ]. Administration of rhTM improved renal function and survival in patients with septic disseminated intravascular coagulation and those with acute kidney injury [ 25 ].…”

NAD+ ameliorates endotoxin‐induced acute kidney injury in a sirtuin1–dependent manner via GSK‐3β/Nrf2 signalling pathway

“…All mice were anaesthetized with 2%~3% isoflurane (R510‐22, RWD Life Science) inhalation for induction and 1.5% isoflurane for maintenance. Wild‐type and NMNAT1 −/− mice were used in the LPS‐induced AKI model by caudal vein injection of LPS (E.coli‐L2630, Sigma) 15 mg/kg diluted in 2 ml saline as described previously 25 . In addition, the mice were intraperitoneally injected with 500 mg/kg NMN (M3501, Sigma, USA) for 7 consecutive days prior to LPS treatment.…”

“…Wild‐type and NMNAT1 −/− mice were used in the LPS‐induced AKI model by caudal vein injection of LPS (E.coli‐L2630, Sigma) 15 mg/kg diluted in 2 ml saline as described previously. 25 In addition, the mice were intraperitoneally injected with 500 mg/kg NMN (M3501, Sigma, USA) for 7 consecutive days prior to LPS treatment. To explore the effect of SIRT1 on LPS‐induced AKI and the involved GSK‐3β/Nrf2 signalling pathway, wild‐type C57BL/6 mice were divided into four groups: control (CON); LPS‐treated mice (LPS); LPS plus SIRT1 selective agonist (SRT‐1720)‐treated mice (LPS + SRT‐1720) and LPS plus SIRT1 specific inhibitor‐treated mice (LPS + EX‐527).…”