Interaction of thrombospondin1 and CD36 contributes to obesity-associated podocytopathy

Abstract

Obesity is associated with podocyte injury and the development of proteinuria. Elevated plasma free fatty acid is one of the characteristics of obesity and has been linked to podocyte dysfunction. However, the mechanisms remain unclear. In the current study, we examined the effect of saturated free fatty acid (FFA) on human podocyte apoptosis and function in vitro. The mechanism and its in vivo relevance were also determined. We found that FFA treatment induced human podocyte apoptosis and dysfunction, which was associated with increased expression of a matricellualr protein-thrombospondin1 (TSP1). FFA stimulated TSP1 expression in podocytes at the transcriptional levels through activation of MAPK pathway. Addition of purified TSP1 to cell culture media induced podocyte apoptosis and dysfunction. Tis effect is though a TGF-β independent mechanism. Moreover, peptide treatment to block TSP1 binding to its receptor-CD36 attenuated FFA induced podocyte apoptosis, suggesting that TSP1/CD36 interaction mediates FFA-induced podocyte apoptosis. Importantly, using a dietinduced obese mouse model, in vivo data demonstrated that obesity-associated podocyte apoptosis and dysfunction were attenuated in TSP1 deficient mice as well as in CD36 deficient mice. Taken together, these studies provide novel evidence that the interaction of TSP1 with its receptor CD36 contributes to obesity - associated podocytopathy.

Exosomal Thrombospondin-1 Disrupts the Integrity of Endothelial Intercellular Junctions to Facilitate Breast Cancer Cell Metastasis

“…Tumor microenvironment, comprising of various proteins, nucleic acids and vesicles, plays a key role in cancer progression to metastasis. TSP1 is one of the extracellular matrix glycoproteins, generally secreted by endothelial cells, fibroblasts, smooth muscle cells, and regulates the signaling pathways of CD47, CD36 and TGF-β [32,33]. The present study demonstrated that TSP1 is one of the important components in carcinoma-derived exosomes and is most likely to be a key molecule responsible for the down-regulation of molecules such as ZO-1 and VE-cadherin involved in the maintenance of epithelial integrity.…”

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.…”

Thrombospondin 1 and Its Diverse Roles as a Regulator of Extracellular Matrix in Fibrotic Disease

“…TSP1 binding to its receptor CD36 is involved in podocyte apoptosis. 81 TSP1 has a pro-inflammatory effect on macrophages by stimulating increased toll-like receptor 4 expression, which in turn induces tumor necrosis factor-α production in a manner blocked by peptides that prevent TSP1-CD36 binding. 82 TSP1 is a known inhibitor of angiogenesis through its ability to downregulate nitric oxide signaling downstream of binding to CD47, and the TSP1-CD47 pathway is well documented to exacerbate ischemiareperfusion injury.…”