Abstract

Accumulating evidence suggests that thrombospondin 1 (TSP1) is an important player in diabetic nephropathy. However, the role of TSP1 in podocyte injury and the development of non-diabetic proteinuric kidney disease is largely unknown. In the current study, by using a well-established podocyte injury model (adriamycin-induced nephropathy mouse model), we examined the contribution of TSP1 to the development of proteinuric kidney disease. We found that TSP1 was up-regulated in the glomeruli, notably in podocytes, in adriamycin injected mice before the onset of proteinuria. ADR treatment also stimulated TSP1 expression in cultured human podocytes in vitro. Moreover, increased TSP1 mediated ADR-induced podocyte apoptosis and actin cytoskeleton disorganization. This TSP1’s effect was through a CD36-dependent mechanism and involved in the stimulation of p38MAPK pathway. Importantly, in vivo data demonstrated that TSP1 deficiency protected mice from ADR induced podocyte loss and foot process effacement. ADR induced proteinuria, glomerulosclerosis, renal macrophage infiltration and inflammation was also attenuated in TSP1 deficient mice. Taken together, these studies provide new evidence that TSP1 contributes to the development of non-diabetic proteinuric kidney disease by stimulating podocyte injury and the progression of renal inflammation.

Highlights

  • Thrombospondin1 (TSP1) belongs to a family of five secreted glycoproteins encoded by separated genes

  • To address the role of TSP1 in podocyte injury and the development of proteinuric kidney disease, first, we studied its expression in glomerulus from experimental focal segmental glomerulosclerosis (FSGS) model-ADR induced nephropathy

  • This data is consistent with studies from primary human FSGS kidney samples showing that injured podocytes expressed more TSP1 in glomeruli [24], suggesting that podocyte is a cellular source of increased glomerular TSP1 in both human and experimental

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Summary

Introduction

Thrombospondin (TSP1) belongs to a family of five secreted glycoproteins encoded by separated genes. It is released from activated platelet and is synthesized and secreted by many cell types including endothelial cells, smooth muscle cells, kidney mesangial cells, tubular cells, and podocytes et al [1]. TSP1 is a 420–450 kDa homotrimer with individual subunits of approximately 145 kDa. It is composed of several domains that can interact with specific cell surface receptors/molecules to modulate cell adhesion, growth, motility, differentiation, and survival [2,3,4,5,6,7]. Accumulating evidence suggests that TSP1 is an important player in a variety of kidney diseases such as ischemia-reperfusion induced kidney injury and obesity/.

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