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Selenium-binding protein-1 in smooth muscle cells is downregulated in a rhesus monkey model of chronic allograft
Jose R Torrealba1, Matthew Colburn, Susan Golner
1Department of Pathology, University of Wisconsin-Madison, WI, USA.
Abstract:
Treating patients with kidney failure by organ transplantation has been extraordinarily successful. Although, 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 lumen of blood vessels. We show that selenium-binding protein-1 (SBP-1), a protein implicated in protein trafficking 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 allografts with CAN. In contrast, the SMC alpha-actin was strongly expressed in the vascular SMC of the same allografts, 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-beta blocked the expression of SBP-1; thus, TGF-beta 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-beta on SMC and in the process of CAN.
Insights
Selenium-binding protein-1 (SBP-1) is crucial in smooth muscle cells (SMC) and may be involved in chronic allograft nephropathy (CAN) after kidney transplants. TGF-beta downregulates SBP-1, potentially contributing to transplant rejection.
Area of Science:
- Nephrology
- Immunology
- Cell Biology
Background:
- Kidney transplantation is successful but often fails long-term due to chronic allograft nephropathy (CAN).
- The molecular mechanisms of CAN remain unclear, but vascular smooth muscle cells (SMC) play a key role in its pathogenesis.
- Selenium-binding protein-1 (SBP-1) is a phosphoprotein found in SMC.
Purpose of the Study:
- To investigate the role of SBP-1 in the pathogenesis of CAN.
- To determine the localization and regulation of SBP-1 in vascular SMC during CAN.
Main Methods:
- Immunohistochemical analysis of SBP-1 and SMC alpha-actin in kidney allografts.
- Assessment of SBP-1 expression in SMC treated with growth factors implicated in CAN, including TGF-beta.
Main Results:
- SBP-1 was primarily localized to SMC in vivo and was heavily tyrosine-phosphorylated.
- SBP-1 was significantly downregulated in vascular SMC of kidney allografts exhibiting CAN.
- Transforming growth factor-beta (TGF-beta) was identified as a factor that blocks SBP-1 expression in SMC.
Conclusions:
- SBP-1 is a phosphoprotein localized in SMC and its downregulation is associated with CAN.
- TGF-beta may regulate SBP-1 expression in SMC, implicating this pathway in the development of CAN.
- SBP-1 is a potential therapeutic target for preventing or treating chronic allograft nephropathy.
