Decorin in renal inflammation and fibrosis – more than an inhibitor of TGF‐β

Abstract

Introduction Decorin, a small leucine‐rich proteoglycan, participates in extracellular matrix assembly and influences cell behaviour by interacting with signalling membrane receptors and TGF‐β. Treatment with decorin has been shown to have beneficial effects in an acute model of mesangioproliferative glomerulonephritis due to interaction with TGF‐β. The underlying mechanisms, however, remain unclear because upon complex formation with TGF‐β, the cytokine's activity may become increased, decreased or not influenced at all. Hence, the objectives of the present study were twofold: firstly, to provide evidence that decorin influences the course and final outcome of renal inflammation and secondly, to find anti‐fibrotic mechanisms of decorin both related and unrelated to the regulation of TGF‐β activity.Results Based on our studies in human diabetic nephropathy, we postulate two regulatory mechanisms by which decorin modulates TGF‐β‐mediated fibrosis: (1) increased quantities of glomerular decorin are synthesized and form complexes with TGF‐β, which then are removed via glomerular capillaries or the urinary tract, and (2) in the presence of type‐I collagen, decorin is able to sequester TGF‐β in the extracellular matrix, thereby withdrawing the cytokine from its cell‐surface receptors. Furthermore, we have compared the evolution of tubulointerstitial fibrosis in wild‐type (WT) and decorin–/– mice in a model of unilateral ureteral obstruction. Without obstruction, kidneys from decorin–/– mice did not differ in any aspect from their WT counterparts. However, already 12 h after obstruction, decorin–/– animals showed lower levels of p27KIP1 and soon thereafter a more pronounced up‐regulation and activation of initiator and effector caspases, followed by enhanced apoptosis of tubular epithelial cells. At later stages, a higher increase of TGF‐β1 became apparent. After 7 days, there was a 15‐fold transient up‐regulation of the related proteoglycan biglycan, which was mainly caused by the appearance of biglycan‐expressing mononuclear cells. Other small proteoglycans showed no similar response. Owing to enhanced degradation of type‐I collagen and increased tubular epithelial cell apoptosis, end‐stage kidneys from decorin–/– animals were more atrophic than WT kidneys.Conclusion These data suggest that decorin exerts beneficial effects on renal inflammation, primarily by influencing the expression of a key cyclin‐dependent kinase inhibitor, thereby limiting the degree of apoptosis and tubular atrophy. In later stages, anti‐fibrotic effects of decorin are based on the regulation of TGF‐β1 expression, mononuclear cell infiltration and collagen turnover.