Renal interstitial fibrosis: a critical evaluation of the origin of myofibroblasts.

Interstitial fibrosis is a common feature of chronic kidney disease, regardless of the etiology of the primary renal syndrome. Moreover, interstitial fibrosis is the strongest morphologic predictor of clinical outcome and is most tightly linked to progression of disease, even though the primary disease may be of glomerular origin. Also, the presence of an interstitial component in chronic kidney disease often indicates an ominous outcome. The incidence of chronic kidney disease has reached epidemic proportions; thus, understanding the pathophysiology of interstitial renal disease is paramount for the development of new therapeutic approaches to slowing progression. Experimental models of renal fibrosis have been essential in determining the mechanisms and sequence of progression of fibrogenesis, including the roles of endothelium, infiltrating leukocytes and myofibroblasts; of profibrogenic cytokine and growth factor release; of tubular injury and atrophy; and of interstitial extracellular matrix accumulation. Over the last decade, considerable attention has been paid to the origin of the myofibroblast, the cell type most responsible for interstitial matrix accumulation. However, the origin(s) of myofibroblasts and how they gain access to the peritubular interstitium has become a matter of controversy and debate. Interstitial myofibroblasts have been proposed to originate from one or more of five sources: resident fibroblasts (pericytes), adventitial fibroblasts, circulating fibrocytes, tubular epithelial-mesenchymal transition (EMT) or endothelial/ mesenchymal transition. To date, EMT has become the pre-eminent theory of the origin of myofibroblasts; however, a role for EMT in renal fibrosis is rigorously challenged by anecdotal and recent scientific evidence. This chapter will briefly discuss the experimental models used to explore interstitial renal disease in general and will then focus on the controversy related to the origin of myofibroblasts.