Selenium-Binding Protein-1 in Smooth Muscle Cells is Downregulated in a Rhesus Monkey Model of Chronic Allograft Nephropathy

Abstract

Treating patients with kidney failure by organ trans- plantation has been extraordinarily successful. Al- though, current immunosuppressants have improved short-term allograft survival, most transplants are eventually lost due to chronic allograft nephropathy (CAN). The molecular mechanisms underlying CAN are poorly understood. Smooth muscle cells (SMC) play a major role in the pathogenesis of CAN by contributing to the thickening of the intima and narrowing of the lu- men of blood vessels. We show that selenium-binding protein-1 (SBP-1), a protein implicated in protein traf- ficking and secretion, is localized primarily to SMC in vivo. SBP-1 was heavily tyrosine-phosphorylated in vivo. Remarkably, SBP-1 was absent or strongly downregulated in vascular SMC in monkey kidney al- lografts with CAN. In contrast, the SMC a -actin was strongly expressed in the vascular SMC of the same al- lografts, indicating that the decrease in SBP-1 was not due to a global decrease in SMC proteins. Out of four growth factors implicated in the pathogenesis of CAN, only TGF-b blocked the expression of SBP-1; thus, TGF-b could regulate the expression of SBP-1 in CAN. These results show that SBP-1 localizes primarily to SMC in vivo and implicate this phosphoprotein in the effects of TGF-b on SMC and in the process of CAN. Key words: Chronic allograft nephropathy, trans- plantation, smooth muscle, selenium-binding protein- 1, vascular rejection, atherosclerosis