Role of proteoglycans in renal chronic transplant dysfunction

PhD ceremony: Mr. K.K. Katta, 12.45 uur, Academiegebouw, Broerstraat 5, Groningen

Dissertation: Role of proteoglycans in renal chronic transplant dysfunction

Promotor(s): prof. G.J. Navis, prof. J.L. Hillebrands

Faculty: Medical Sciences

Kidney transplantation is the best treatment for patients with end stage renal failure, in terms of quality of life and life expectancy. Chronic transplant dysfunction (CTD) is associated with decline in kidney function over time and is related to progressive tissue remodeling in the transplanted kidney. Proteoglycans (PGs) have been highly implicated in tissue remodeling such as development, adhesion, migration, growth, wound healing and repair processes, proliferation and fibrosis. This implies that targeting proteoglycan function might provide a strategy to combat CTD-associated tissue remodeling. The data presented in this thesis show the involvement of PGs in CTD tissue remodeling. We showed an upregulation of the heparan sulfate PGs collagen type XVIII and perlecan and chondroitin sulfate PG versican in rat renal allografts. The binding properties of the upregulated PGs has increased upon renal allotransplantation. Perlecan and FGF2 were found to be upregulated in renal allografts. The functional and mechanistical roles of these PGs were studied in vitro using rat glomerular mesangial cells. The results showed that PGs mediated FGF2-dependent proliferation of mesangial cells. Treatment with non-anti-coagulant heparin (RO-heparin) showed beneficial effects after rat renal transplantation. Considering the molecular mechanisms behind neointima formation, we showed that in response to allogeneic transplantation there will be medial dedifferentiation, probably mediated by PDGF-B. Lastly we showed that syndecan-1, a trans-membrane cell surface heparan sulfate PG, is involved in tubular regeneration and repair after renal transplantation and ischemia/reperfusion which correlated with better graft function and survival. Overall PGs are crucially involved in tissue remodeling after transplantation and promising intervention molecules to retard CTD.