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Mechanisms of tubulointerstitial fibrosis

Iwano, Masayukia; Neilson, Eric Gb

Current Opinion in Nephrology and Hypertension: May 2004 - Volume 13 - Issue 3 - p 279-284
Renal immunology and pathology

Purpose of review Tubulointerstitial fibrosis is the final common pathway to end-stage renal disease. Understanding the mechanisms of tubulointerstitial fibrosis is essential in establishing novel therapeutic strategies for the prevention or arrest of progressive kidney diseases. The present review focuses on a newly proposed mechanism of tubulointerstitial fibrosis, one that emphasizes the roles of epithelial-mesenchymal transition and cellular activation.

Recent findings Among the cells that accumulate in the renal interstitium, fibroblasts are the principal effectors mediating tubulointerstitial fibrosis. By contrast, the phagocytosis of extracellular matrix and apoptotic cells by macrophages may actually exert a beneficial effect. Interstitial fibroblasts are more heterogeneous than expected, and during renal fibrosis new fibroblasts are derived mainly through epithelial-mesenchymal transition. The intracellular signaling pathways leading to initiation of epithelial-mesenchymal transition remain largely unknown, though recent studies have identified β-catenin and Smad3 activation of lymphoid enhancer factor, integrin-linked kinase, and small GTPases and mitogen-activated protein kinases as key components. Transforming growth factor-β is believed to be a critical fibrogenic factor, but recent studies have also focused on transforming growth factor-β independent pathways as mechanisms of tubulointerstitial fibrosis. As the mechanisms underlying tubulointerstitial fibrosis leading to epithelial-mesenchymal transition have been identified, so have cytokines that efficiently antagonize renal fibrosis, particularly bone morphogenic protein-7 and hepatocyte growth factor.

Summary In combination with traditional angiotensin converting enzyme inhibitors, newly identified cytokines may eventually form the basis for new therapeutic strategies aimed at inhibiting the progression of renal disease.

aFirst Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan, and bDepartments of Medicine and Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA

Correspondence to Eric G. Neilson MD, Hugh Jackson Morgan Professor of Medicine and Cell and Developmental Biology, Chairman, Department of Medicine, D-3100 MCN, Vanderbilt University School of Medicine, Nashville, TN 37232-2358, USA Tel: +1 615 322 3146; fax: +1 615 343 9391; e-mail:

© 2004 Lippincott Williams & Wilkins, Inc.