Incipient renal transplant dysfunction associates with tubular syndecan-1 expression and shedding

Abstract

Syndecan-1 is a transmembrane heparan sulfate proteoglycan involved in regenerative growth and cellular adhesion. We hypothesized that the induction of tubular syndecan-1 is a repair response to incipient renal damage in apparently stable, uncomplicated renal transplant recipients. We quantified tubular syndecan-1 in unselected renal protocol biopsies taken 1 yr after transplantation. Spearman rank correlation analysis revealed an inverse correlation between tubular syndecan-1 expression and creatinine clearance at the time of biopsy (r = -0.483, P < 0.03). In a larger panel of protocol and indication biopsies from renal transplant recipients, tubular syndecan-1 correlated with tubular proliferation marker Ki67 (r = 0.518, P < 0.0001). In a rat renal transplantation model, 2 mo after transplantation, mRNA expression of syndecan-1 and its major sheddase, A disintegrin and metalloproteinase-17, were upregulated (both P < 0.03). Since shed syndecan-1 might end up in the circulation, in a stable cross-sectional human renal transplant population (n = 510), we measured plasma syndecan-1. By multivariate regression analysis, we showed robust independent associations of plasma syndecan-1 with renal (plasma creatinine and plasma urea) and endothelial function parameters (plasma VEGF-A, all P < 0.01). By various approaches, we were not able to localize syndecan-1 in vessel wall or endothelial cells, which makes shedding of syndecan-1 from the endothelial glycocalyx unlikely. Our data suggest that early damage in transplanted kidneys induces repair mechanisms within the graft, namely, tubular syndecan-1 expression for tubular regeneration and VEGF production for endothelial repair. Elevated plasma syndecan-1 levels in renal transplantation patients might be interpreted as repair/survival factor related to loss of tubular and endothelial function in transplanted kidneys.

Plasma syndecan-1 in hemodialysis patients associates with survival and lower markers of volume status

“…Syndecan-1 is suggested as a tissue repair response marker. Upon injury, syndecan-1 is upregulated and involved in tissue repair responses in different organs such as the skin (11) or the kidneys (2,8). As a result of cellular shedding, an increase of plasma syndecan-1 levels can be acutely induced by a number of different stimuli such as major surgery, inflammatory insults, ischemia-reperfusion, shock, and also during HD (16,24), leading to a lower responsiveness status of the cells of origin.…”

“…Syndecan-1 is expressed in many cell types during development but is downregulated in most cells after birth (6). In adults, syndecan-1 is mainly expressed by hepatocytes (28), epithelial cells (2), and plasma cells (30). Elevated plasma syndecan-1 is usually interpreted as endothelial glycocalyx loss and/or shedding from the (renal) epithelium and/or the liver (1,2,43).…”

“…In adults, syndecan-1 is mainly expressed by hepatocytes (28), epithelial cells (2), and plasma cells (30). Elevated plasma syndecan-1 is usually interpreted as endothelial glycocalyx loss and/or shedding from the (renal) epithelium and/or the liver (1,2,43). Shedding is executed by matrix metalloproteinases (MMPs) and by disintegrin and metalloproteinases (ADAMs), such as MMP9 and ADAM17 (22).…”

Danger signals in regulating the immune response to solid organ transplantation

“…Studies in human renal transplant recipients have confirmed the clinical relevance of perlecan expression in kidney rejection, as higher serum or urinary levels of the perlecan C-terminal fragment associate with acute vascular rejection or advanced chronic allograft nephropathy, respectively (71,72). A recent translational study by Adepu and colleagues also implicated the HS syndecan-1 as important in contributing to graft outcomes in experimental and clinical kidney transplantation (73).…”

Role of syndecan-1 in the interaction between dendritic cells and T cells

“…While the immunomodulatory properties of Sdc-1 have been established in mouse models of inflammation, there is little data on the potential role of Sdc-1 in transplantation. In kidney transplant patients and animal models, increased tubular Sdc-1 expression was suggested to promote tubular survival and repair, while increased Sdc-1 plasma levels reflected early loss of tubular function (14, 19). The effect of Sdc-1 deficiency on allograft survival was not investigated.…”