From Fibrosis to Sclerosis

Abstract

During the 1990s, a general consensus emerged about major signaling mechanisms involved in stimulating mesangial cell synthesis of ECM proteins (Fig. 1). In this consensus view, high extracellular glucose induces an increase in glucose uptake via increased expression of the facilitative glucose transporter GLUT1 (5,6). The resultant enhancement in glucose metabolic flux leads to activation of a number of metabolic pathways that result in increased advanced glycation end product and oxidative stress generation (7–9), which in turn activate a number of signaling pathways that lead to enhanced ECM production directly via protein kinase β stimulation (10,11) of AP-1 transcriptional activation, extracellular signal–related kinase (ERK) pathways, and, critically, transforming growth factor (TGF)-β1 synthesis (12,13), which in an autocrine and paracrine fashion stimulates its signaling pathways to stimulate ECM protein synthesis (Fig. 1). These responses triggered by TGF-β1 appear to be the final common pathway by which nephrosclerosis occurs. While of critical importance in the development of nephrosclerosis in diabetes and in most fibrotic diseases of the kidney, the role of TGF-β and its signaling mechanisms have been the subject of several recent reviews on diabetic nephropathy (14,15) and will not be further detailed in this review, which focuses on mechanisms that have been recently described, many of which trigger or participate in TGF-β responses.