Simvastatin increases ADAMTS13 expression in podocytes

Abstract

Introduction: ADAMTS13 is a specific von Willebrand factor-cleaving protease. Severe deficiency of ADAMTS13 is the main cause of thrombotic thrombocytopenic purpura. ADAMTS13 is mainly synthesized and released from hepatic stellate cells and endothelial cells, but is also expressed in other cells, including kidney podocytes. Simvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, has a beneficial effect on atherosclerosis and also has anti-inflammatory and antithrombotic properties. A recent study indicates that ADAMTS13 reduces inflammatory plaque formation during early atherosclerosis in mice. In our study, we investigated the effects of simvastatin on inflammatory cytokines-induced ADAMTS13 expression in podocytes.

Materials and methods: A conditionally immortalized mouse podocyte cell line was utilized to study the expression of ADAMTS13 in podocytes. The influence of TNF-α, IL-4, IL-6 and simvastatin on ADAMTS13 was investigated. ADAMTS13 mRNA levels in podocytes were measured by using real-time PCR and protein levels were detected by Western blotting.

Results: Simvastatin significantly up-regulated the expression levels of ADAMTS13 mRNA and protein in podocytes. IL-6 decreased ADAMTS13 expression, and TNF-α had no significant effects on ADAMTS13 expression in podocytes. IL-4 reduced ADAMTS13 mRNA expression but not its protein level. Simvastatin was able also reversed the inhibitory effect of IL-6.

Conclusions: We demonstrate that simvastatin increases the expression of ADAMTS13 in a dose-dependent manner in podocytes, which likely contributes to the antithrombotic property of statin. Different inflammatory cytokines have different effects on the levels of ADAMTS13 mRNA expression and protein within podocytes.

Keywords: 3-hydroxy-3-methylglutaryl coenzyme A; A disintegrin-like and metalloprotease with thrombospondin type 1 repeats 13; ADAMTS13; HMG-CoA; IL-4; IL-6; TNF-α; TTP; VWF; interleukin-4; interleukin-6; podocyte; simvastatin; thrombotic thrombocytopenic purpura; tumor necrosis factor-α; von Willebrand factor.