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  • Review Article
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Cellular and molecular mechanisms of renal fibrosis

Nature Reviews Nephrology volume 7, pages 684–696 (2011)Cite this article

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Abstract

Renal fibrosis, particularly tubulointerstitial fibrosis, is the common final outcome of almost all progressive chronic kidney diseases. Renal fibrosis is also a reliable predictor of prognosis and a major determinant of renal insufficiency. Irrespective of the initial causes, renal fibrogenesis is a dynamic and converging process that consists of four overlapping phases: priming, activation, execution and progression. Nonresolving inflammation after a sustained injury sets up the fibrogenic stage (priming) and triggers the activation and expansion of matrix-producing cells from multiple sources through diverse mechanisms, including activation of interstitial fibroblasts and pericytes, phenotypic conversion of tubular epithelial and endothelial cells and recruitment of circulating fibrocytes. Upon activation, matrix-producing cells assemble a multicomponent, integrin-associated protein complex that integrates input from various fibrogenic signals and orchestrates the production of matrix components and their extracellular assembly. Multiple cellular and molecular events, such as tubular atrophy, microvascular rarefaction and tissue hypoxia, promote scar formation and ensure a vicious progression to end-stage kidney failure. This Review outlines our current understanding of the cellular and molecular mechanisms of renal fibrosis, which could offer novel insights into the development of new therapeutic strategies.

Key Points

  • Despite having various initial causes, renal fibrogenesis is a converging and highly dynamic process, which consists of four overlapping phases: priming, activation, execution and progression

  • After a sustained injury, nonresolving inflammation sets up a fibrogenic stage (priming) and triggers the activation and expansion of matrix-producing fibroblasts from multiple sources through a range of mechanisms

  • Upon activation, the matrix-producing cells build a multicomponent, integrin-associated, ternary protein complex, which integrates various fibrogenic signals and orchestrates the production of extracellular matrix and its assembly

  • Many cellular and molecular events, such as tubular atrophy, vascular rarefaction and hypoxia, promote the progressive loss of kidney function and determine the outcome of renal fibrosis

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Figure 1: Major events in renal interstitial fibrogenesis.
Figure 2: Multiple origins of myofibroblasts have been proposed in renal fibrosis.
Figure 3: A multicomponent, integrin-associated protein complex constitutes the molecular machinery that integrates various fibrogenic signals and orchestrates matrix production and assembly.

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Acknowledgements

I apologize to all colleagues whose important findings could not be cited due to space limitations. Our works described in this Review were supported by the National Institutes of Health grants DK064005 and DK071040.

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    Youhua Liu

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Liu, Y. Cellular and molecular mechanisms of renal fibrosis. Nat Rev Nephrol 7, 684–696 (2011). https://doi.org/10.1038/nrneph.2011.149

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