FTY720 attenuates tubulointerstitial inflammation and fibrosis in subtotally nephrectomized rats

Abstract

Tubulointerstitial fibrosis is a common pathway that leads to kidney failure, and persistent tubulointerstitial inflammation is a key event in the development of tubulointerstitial fibrosis. The new immunosuppressive drug FTY720 modifies lymphocyte migration into injured tissues by sequestering lymphocytes within secondary lymphoid organs. However, its therapeutic effect on tubulointerstitial inflammation and fibrosis had not been well understood. This study was designed to explore the effect of FTY720 on tubulointerstitial inflammation and fibrosis in subtotally nephrectomized (SNX) rats. In total, 24 male Sprague-Dawley rats were used. Seven days after 5/6 nephrectomy, rats were randomized to FTY720 (1 mg/kg/d) and placebotreated groups. Sham-operated rats served as controls. FTY720 significantly attenuated the rise in proteinuria, serum creatinine, urea nitrogen and N-acetyl-b-D-glucosaminidase activity in SNX rats, and reduced the count of peripheral white blood cells and lymphocytes in SNX rats. Morphological analysis revealed that there was severe tubulointerstitial inflammation and fibrosis in SNX group and much more tubulointerstitial infiltrating inflammatory cells with high expression of CD3, CD4, CD8, CD20, CD68, CD163 and CCR-7 in SNX group, as compared with the controls, but the lesions were attenuated significantly by treatment with FTY720. Furthermore, the expressions of proinflammatory molecules (IL-6, TNF-a and MCP-1), profibrotic molecule (TGF-b1) and production of extracellular matrix proteins such as fibronectin and types I and III collagens were upregulated in SNX rats. FTY720 administration significantly reduced these abnormalities. In summary, FTY720 exerts therapeutic effects on tubulointerstitial fibrosis in SNX rats by inhibiting the tubulointerstitial inflammatory response.

Urinary collagen degradation products as early markers of progressive renal fibrosis

“…a model of proteinuria-induced tubulointerstitial fibrosis). S1P receptor modulator FTY720 (FINGOLIMOD ® ) has been shown to have an inhibitory effect on fibrosis and on T cell mediated inflammation [26–29]. Therefore this intervention was used to distinguish the effects of anti-fibrotic treatment on different components of ECM remodeling pathways in the kidneys, as well as on collagen fragments in plasma and urine.…”

Pleiotropic FTY720 Is a Specific and Potent Therapy for Hypertrophic Scars

“…FTY720, a well-documented immunosuppressive agent, is associated with a variety of biological activities, including anti-allograft rejection (Gao et al, 2014;Koch et al, 2016), anticancer (Estrada-Bernal et al, 2012;Lu et al, 2014), anti-inflammation (Aktas et al, 2010;Xu et al, 2014), and antifibrosis (Kramer et al, 2009;Ni et al, 2013). These activities were achieved through the alteration of multiple cell phenotypes, such as viability, proliferation, apoptosis, migration/invasion, and/or epithelial mesenchymal transition, depending on specific disease conditions (Bohler et al, 2009;Lu et al, 2014;Wolf et al, 2009;Zhang et al, 2010;Zhang et al, 2014;Zhang L et al, 2015).…”

“…FTY720 also induces apoptosis in multiple cancer cell lines (Chen et al, 2014;Estrada-Bernal et al, 2012;Lu et al, 2014;Marvaso et al, 2014;Zhang et al, 2010), showing promise as an anticancer therapy. Recent studies showed that FTY720 controls interstitial fibrosis and extracellular matrix accumulation by inhibiting the production of inflammatory cytokines, suggesting its antifibrotic potential (Ni et al, 2013). In this study, we hypothesized that FTY720 attenuates HS formation by directly targeting HSFs.…”

FTY720 inhibits tubulointerstitial inflammation in albumin overload-induced nephropathy of rats via the Sphk1 pathway

“…Additionally, Jo et al described its cytoprotective effects in proximal tubular cells during renal ischemia-reperfusion injury [11] . More recently, we demonstrated that FTY720 exerts an anti-fibrotic effect in subtotally nephrectomized rats [10] . The mechanism by which FTY720 mediates protection in proteinuric nephropathy is not completely understood.…”

“…FTY720 treatment alleviated this inflammatory response [3] . Previous studies have demonstrated a remarkable protective effect of FTY720 in models of 5/6 nephrectomized renal failure [10] , acute renal ischemia-reperfusion injury [11] and diabetic nephropathy [12] . However, the precise effect of FTY720 on proteinuria-induced tubulointerstitial inflammation has not been well addressed.…”