Fibroblasts and myofibroblasts in renal fibrosis

Abstract

Interstitial fibrosis, associated with extensive accumulation of extracellular matrix constituents in the cortical interstitium, is directly correlated to progression of renal disease. The earliest histological marker of this progression is the accumulation in the interstitium of fibroblasts with the phenotypic appearance of myofibroblasts. These myofibroblasts are contractile cells that express alpha smooth muscle actin and incorporate it into intracellular stress fibres. Although fibroblasts are histologically visible in normal kidneys, there are relatively few of them and proximal tubular epithelial cells predominate. In progressive disease, however, the interstitium becomes filled with myofibroblasts. In this review, we will examine the phenotype and function of fibroblasts and myofibroblasts in the cortical interstitium and the processes that may modulate them.

Figure 1

Following an increase in mechanical tension, fibroblasts become activated and acquire a migratory phenotype termed the proto-myofibroblast. Proto-myofibroblasts are characterized by the presence of stress fibres containing filamentous actins, and synthesis of ED-A fibronectin. In the presence of prolonged mechanical tension, ED-A fibronectin, and TGF-β1 further differentiation occurs to a contractile phenotype, termed a differentiated myofibroblast, characterized by the expression of alpha smooth muscle actin (adapted from Tomasek et al. 2002).

Figure 2

TGF-β1-dependent phenotypic activation triggers two distinct but cooperative pathways that involve TGF-R/Smad2 activation and EGF-mediated EGF-R/ERK mitogen-activated protein kinase activation. HAS2-dependent HA synthesis is also initiated by EGF/EGFR binding. The subsequent binding of HA to CD44 facilitates CD44 association with the EGFR. This association triggers phosphorylation of ERK1 and ERK2, which promotes cellular differentiation when combined with Smad activation (adapted from Simpson et al. 2009b). EGFR, epidermal growth factor receptor; HA, hyaluronic acid.