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  • Review Article
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Fibroblast activation and myofibroblast generation in obstructive nephropathy

Nature Reviews Nephrology volume 5, pages 319–328 (2009)Cite this article

Abstract

Obstructive nephropathy is a major cause of renal failure, particularly in newborn babies and children. After urinary tract obstruction, and under the influence of mechanical forces and cytokines produced by tubular cells and cells that have infiltrated the interstitium, resident fibroblasts undergo activation and myofibroblasts are generated from bone-marrow-derived cells, pericytes and endothelial cells. In addition, selected tubular epithelial cells can become fibroblast-like cells via epithelial–mesenchymal transition. This transition is characterized by downregulation of epithelial marker proteins such as E-cadherin, zonula occludens 1 and cytokeratin; loss of cell-to-cell adhesion; upregulation of mesenchymal markers including vimentin, α-smooth muscle actin and fibroblast-specific protein 1; basement membrane degradation; and migration to the interstitial compartment. All the events of epithelial–mesenchymal transition are strictly regulated by complex signaling pathways. Myofibroblasts and activated fibroblasts proliferate and produce large amounts of extracellular matrix, which accumulates in the tubular interstitium; together with tubular atrophy, this accumulation leads to interstitial fibrosis. This Review examines the molecular mechanisms of fibroblast activation and epithelial–mesenchymal transition, processes that seem to be promising targets for the prevention, or even reversal, of interstitial fibrosis and renal dysfunction associated with obstructive nephropathy.

Key Points

  • Obstructive nephropathy, a leading cause of chronic kidney disease in children, is characterized by inflammation, tubular atrophy and interstitial fibrosis

  • Activation of local fibroblasts and generation of myofibroblasts from epithelial cells (via epithelial–mesenchymal transition [EMT]), pericytes, endothelial cells and bone-marrow-derived cells are key processes in tubulointerstitial fibrosis

  • Data from rodent models of unilateral ureteral obstruction and in vitro studies have shed new light on the molecular mechanisms that underlie these processes

  • Fibroblast activation and EMT are induced by mechanical forces and cytokines such as transforming growth factor β, platelet-derived growth factor, fibroblast growth factor and activin A

  • EMT is strictly regulated by several signaling pathways that involve small GTPases, mitogen-activated protein kinases, phosphatidylinositol 3 kinase–Akt, glycogen synthase kinase 3β, integrin-linked kinase–PINCH and nuclear factor κB, among other molecules

  • Knowledge of the molecular mechanisms responsible for fibroblast activation and EMT is essential for the development of pharmacological strategies to prevent or treat interstitial fibrosis associated with obstructive nephropathy

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Figure 1: Histological alterations observed in the kidney after unilateral ureteral obstruction in mice.
Figure 2: Origins of activated fibroblasts and myofibroblasts in the obstructed kidney.
Figure 3: Stages of epithelial–mesenchymal transition.
Figure 4: Signaling pathways involved in the initial steps of epithelial–mesenchymal transition.

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Acknowledgements

The authors' studies have been supported by grants from Ministerio de Educación, Turismo y Deportes (BFU2004-00285/BFI, and SAF2007-63,893), Junta de Castilla y León (SA 001/C05), and Instituto de Salud Carlos III (RETIC RedinRen RD/0016). The authors sincerely thank Dr Angela Nieto for her critical reading of the manuscript and for her suggestions, which greatly helped to improve the manuscript.

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  1. Departamento de Fisiología y Farmacología, Instituto “Reina Sofía” de investigación Nefrológica, Universidad de Salamanca, Salamanca, Spain

    María T. Grande & José M. López-Novoa

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Grande, M., López-Novoa, J. Fibroblast activation and myofibroblast generation in obstructive nephropathy. Nat Rev Nephrol 5, 319–328 (2009). https://doi.org/10.1038/nrneph.2009.74

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