Thrombospondin 1 Deficiency Ameliorates the Development of Adriamycin-Induced Proteinuric Kidney Disease

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.

CD36 in chronic kidney disease: novel insights and therapeutic opportunities

“…136 Similarly, in an adriamycin-induced nephropathy mouse model of focal segmental glomerulosclerosis, TSP1 expression increased in injured podocytes and led to CD36-dependent apoptosis via activation of the p38MAPK pathway. 137 In a model of diet-induced obesity, podocyte apoptosis and dysfunction were attenuated in TSP1-deficient and in CD36-deficient mice, suggesting that the interaction of TSP1 with CD36 contributes to obesity-associated podocytopathy 138 . Moreover, blocking TSP1 binding to CD36 using peptide treatment attenuated fatty-acid-induced podocyte apoptosis, suggesting that the TSP1/CD36 interaction mediates this process.…”

“…In addition to tubules, CD36 is also upregulated in podocytes during proteinuric injury in experimental models and human podocytes, and blockade of CD36 on podocytes in vitro led to an improvement in health with less apoptosis and oxidative stress. 12,22,137,138,190 Blockade of CD36-dependent pathways, therefore, holds great promise as a therapeutic strategy for a variety of kidney diseases.…”

Role of thrombospondin 1 in liver diseases

“…CD36 is one of TSP1's receptors. It exists on many cell types such as endothelial cells, vascular smooth muscle cells, adipocytes, macrophages, tubular cells, and podocytes . CD36 interacts with the type 1 repeats of TSP1 to regulate cellular functions in many ways.…”

“…It activates the p38 mitogen‐activated protein kinase (MAPK) pathway and induces endothelial cell apoptosis, which negatively regulates angiogenesis . Thrombospondin 1 and CD36 interaction also activates the p38 MAPK pathway in kidney podocytes and is involved in podocyte apoptosis . On macrophages, TSP1 binds to CD36 and leads to macrophage activation .…”

应用动物模型探索肾脏疾病作用机制和潜在治疗靶点

“…Most rat species are susceptible to low doses of ADR ranging from 1.5–7.5 mg/kg ( Lee & Harris, 2011 ), whereas most mouse strains are resistant to ADR. To produce a successful model, higher doses of ADR are required, for example 9.8–12 mg/kg in male BALB/C ( Wada et al, 2016 ) and 13–25 mg/kg in C57BL/c mice ( Cao et al, 2010 ; Hakroush et al, 2014 ; Jeansson et al, 2009 ; Maimaitiyiming et al, 2016 ; Wang et al, 2000 ).…”