The Mechanisms of Polyomavirus BK Infection-Induced Renal Fibrosis

Human polyomavirus BK (BKV) infection in renal transplant patients is a serious problem since BKV infection 10% of patients develop BKV-associated nephropathy (BKVAN) and half of them will inevitably lose their allograft function. It has been recently shown that prominent collagen deposition in the kidney is found in patients with BKVAN and renal fibrosis can predict subsequent allograft dysfunction. Nevertheless, it lacks evidence showing a causal relationship between BKV infection and renal fibrosis. It is therefore important to investigate whether BKV infection can directly induce renal fibrosis. Our preliminary results demonstrated that administration of BKV to human renal proximal tubular cells, HK-2, led to an increase in fibronectin production, suggesting a direct effect of BKV infection on induction of extracellular matrix (ECM) protein production, an important characteristic of renal fibrosis. In addition, transfection of cells with BKV capsid proteins VP1, VP2 and VP3 also increased fibronectin production, further confirming the stimulatory effect of BKV on ECM accumulation. Transforming growth factor-�1 (TGF-�1), a profibrogenic factor, plays a central role in development of renal fibrosis. We and others have demonstrated in several models that TGF-�1 facilitates ECM protein production through the Smad signaling pathway. Abrogation of the Smad signals by transfection of cells with small interfering RNA or the dominant-negative Smads alleviates progression of renal fibrosis. Whether TGF-�1/the Smad signaling pathway is implicated in BKV or its components-induced ECM accumulation will be investigated in this project. Innate immunity has recently been shown to play a pivotal role in development of tissue fibrosis. For example, TLR4 is crucial for hepatic fibrogenesis as TLR4-mutant mice develop less severe liver fibrosis after bile duct ligation or thioacetamide injection. We have recently found that TLR2 is indispensable in leptospirosis-mediated increase of fibronectin production. We recently found that BKV infection induced TLR9 expression in HK-2 cells. Whether TLRs and their downstream mediators, MyD88 and TRAF6, are essential for the BKV and its components-induced increase of fibronectin production will be elucidated. Finally, since murine polyomavirus bear many similarities to human BKV and provided by that inoculation of murine polyomavirus into mice leads to high expression of viruses in the kidney, we will inoculate murine polyomavirus through intra-peritoneal and intra-renal arterial injection to determine whether BKV infection can result in an increase in ECM deposition in the kidney. This project can shed light on the machinery of BKV-induced renal fibrosis and may provide possible therapeutic targets to prevent progression of renal fibrosis. Using this animal model to mimic human BKVAN to confirm the association of BKV infection and renal fibrosis can generate a useful model for the future development of therapeutic agents to prevent progression of BKVAN.

Project ID:PC9907-2534
External Project ID:NSC99-2314-B182-005-MY3