Bone morphogenetic protein activity and connective tissue growth factor in renal and vascular disease

Abstract

Response to renal injury is dependent on growth factors that determine how resident cells act, which cells are attracted to the site of injury, and how these resident cells, together with infiltrating cells and their surrounding matrix act together. These mechanisms are not confined to the kidney and also apply to other tissues, including the vasculature. Chronic injury can induce an inappropriate response to injury, where the growth factors are out of balance, and excessive scar formation occurs instead of appropriate regeneration and repair. Diabetes is an important cause of chronic tissue injury, leading to both macrovascular disease (e.g. stroke) and microvascular disease (e.g. diabetic nephropathy). Bone morphogenetic proteins (BMPs) are on the ‘good’ side of the growth factor balance. In the kidney, BMPs are important for maintenance of functional epithelium and for counteracting profibrotic responses. Connective tissue growth factor (CTGF), on the other side of the balance, promotes fibrosis. This thesis describes BMP signalling activity and CTGF involvement in tissue response to injury in renal fibrosis, diabetic nephropathy and during atherosclerotic plaque remodelling. Using the BRE:gfp reporter mouse, we directly visualized the distribution of transcriptional activity downstream of BMP signalling in healthy kidneys and in two distinct models of kidney disease. We conclude that BMP transcriptional activity is much more restricted than previously suggested, and its response to injury varies according to cell type and nephron segment. In glomeruli of human diabetic kidneys, BMP signalling activity was decreased together with an increase of CTGF. These findings suggest that overexpression of CTGF might be an important determinant of the loss of BMP signalling activity in human diabetic nephropathy. To better understand the meaning of urinary CTGF as a biomarker in diabetes we evaluated which factors contribute to elevated uCTGF in this disease. We investigated the renal handling of CTGF in diabetic mice, and the relation between urinary CTGF levels and tubular dysfunction in type 1 diabetic patients. Our results suggest that the majority of uCTGF derives from local production, and tubular damage is an important determinant of uCTGF. Urinary CTGF may therefore be a promising biomarker, integratedly reflecting local intrarenal fibrotic processes and tubular functional status. We next evaluated whether genetic lowering of CTGF in a long-term diabetes model protects against diabetic nephropathy. Unexpectedly, we found that development of an advanced renal phenotype in long-term streptozotocin-induced diabetes, as evidenced by albuminuria, mesangial matrix increase and tubulointerstitial damage, was not prevented by a 50% reduced CTGF expression. CTGF is known to play a role not only in (diabetic) renal injury, but also in the development of atherosclerosis. In a cross-sectional study we obtained evidence that following stroke CTGF may contribute to development of a more stable plaque phenotype. In conclusion, data in this thesis provide a better understanding of the localization and activity of BMP and CTGF in chronic tissue injury such as diabetic nephropathy and atherosclerosis. These findings could help guide the development of new therapies to halt chronic kidney disease and stabilize atherosclerotic plaques.