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Cellular and molecular mechanisms in kidney fibrosis
Jeremy S. Duffield
Jeremy S. Duffield
Published June 2, 2014
Citation Information: J Clin Invest. 2014;124(6):2299-2306. https://doi.org/10.1172/JCI72267.
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Review Series Article has an altmetric score of 36

Cellular and molecular mechanisms in kidney fibrosis

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Abstract

Fibrosis is a characteristic feature of all forms of chronic kidney disease. Deposition of pathological matrix in the interstitial space and within the walls of glomerular capillaries as well as the cellular processes resulting in this deposition are increasingly recognized as important factors amplifying kidney injury and accelerating nephron demise. Recent insights into the cellular and molecular mechanisms of fibrogenesis herald the promise of new therapies to slow kidney disease progression. This review focuses on new findings that enhance understanding of cellular and molecular mechanisms of fibrosis, the characteristics of myofibroblasts, their progenitors, and molecular pathways regulating both fibrogenesis and its resolution.

Authors

Jeremy S. Duffield

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Figure 3

Factors regulating and perpetuating FOXD1-lineage differentiation to myofibroblasts.

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Factors regulating and perpetuating FOXD1-lineage differentiation to myo...
Shown is the initiation of the fibrogenic process, the mechanisms that perpetuate the fibrogenic state, and the consequences of myofibroblast persistence. FOXD1-lineage fibroblasts and pericytes in the interstitial space or attached to endothelium, respectively, respond to signals of endothelial or epithelial injury in a bidirectional manner, including PDGFR-β and -α engagement, which triggers detachment, spreading, migration, and differentiation to myofibroblasts. This process can resolve, but the extent of reversion or other mechanisms of myofibroblast disappearance remain unclear. Some studies propose that a circulating leukocyte also contributes to myofibroblasts, but it remains poorly characterized. Myofibroblasts respond to growth factors, plasma factors, and environmental cues to proliferate, deposit fibrillar matrix, and contract. Expression of metalloproteinases, including ADAMTS family members and their regulators, coordinates detachment, migration, formation of collagen fibrils; factors regulating matrix turnover and degradation including FAP and CTHRC1 favor matrix accumulation. Myofibroblasts are a potent source of cytokines and chemokines and metabolic products, which regulate the inflammatory response. As injury persists, myofibroblasts undergo transcriptional and miRNA reprogramming that contributes to their persistence in an activated state. A subpopulation of myofibroblasts may utilize Endo180 to degrade and resorb pathological matrix, which promotes resolution. The fate of myofibroblasts is currently unclear, but resolution of fibrosis may involve reversion, cell death, or possibly senescence.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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