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The fibrogenic niche in kidney fibrosis: components and mechanisms

Abstract

Kidney fibrosis, characterized by excessive deposition of extracellular matrix (ECM) that leads to tissue scarring, is the final common outcome of a wide variety of chronic kidney diseases. Rather than being distributed uniformly across the kidney parenchyma, renal fibrotic lesions initiate at certain focal sites in which the fibrogenic niche is formed in a spatially confined fashion. This niche provides a unique tissue microenvironment that is orchestrated by a specialized ECM network consisting of de novo-induced matricellular proteins. Other structural elements of the fibrogenic niche include kidney resident and infiltrated inflammatory cells, extracellular vesicles, soluble factors and metabolites. ECM proteins in the fibrogenic niche recruit soluble factors including WNTs and transforming growth factor-β from the extracellular milieu, creating a distinctive profibrotic microenvironment. Studies using decellularized ECM scaffolds from fibrotic kidneys show that the fibrogenic niche autonomously promotes fibroblast proliferation, tubular injury, macrophage activation and endothelial cell depletion, pathological features that recapitulate key events in the pathogenesis of chronic kidney disease. The concept of the fibrogenic niche represents a paradigm shift in understanding of the mechanism of kidney fibrosis that could lead to the development of non-invasive biomarkers and novel therapies not only for chronic kidney disease, but also for fibrotic diseases of other organs.

Key points

  • Kidney fibrosis initiates at certain focal sites in which the fibrogenic niche is formed; this niche provides a specialized microenvironment that triggers fibroblast activation and induces fibrotic lesions.

  • The structural elements of the fibrogenic niche include kidney resident and infiltrated inflammatory cells, extracellular matrix (ECM) network, extracellular vesicles, soluble factors and metabolites.

  • The fibrogenic niche is orchestrated by a specialized ECM network that consists of structurally unrelated, de novo-induced matricellular proteins such as tenascin C, connective tissue growth factor, fibrillin 1 and periostin.

  • Decellularized ECM scaffolds from fibrotic kidneys spontaneously promote fibroblast proliferation, tubular epithelial-to-mesenchymal transition, macrophage activation and endothelial cell apoptosis, and therefore recapitulate major events in the pathogenesis of chronic kidney disease.

  • Components of the fibrogenic niche such as tenascin C recruit various soluble factors from the extracellular milieu, including WNTs, hedgehog and transforming growth factor-β, resulting in a distinctive microenvironment with high levels of profibrotic factors.

  • The development of therapies that target and disrupt the formation of the fibrogenic niche could be a novel and effective strategy for the treatment of fibrotic chronic kidney disease.

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Fig. 1: Renal fibrosis initiates at distinctive focal sites of the kidney parenchyma.
Fig. 2: Cellular and molecular components of the kidney fibrogenic niche.
Fig. 3: Modes of action of matricellular proteins.
Fig. 4: Potential clinical implications of the kidney fibrogenic niche hypothesis.

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Acknowledgements

The authors’ work was supported by the National Natural Science Foundation of China (NSFC) grant 81920108007, National Institutes of Health grant DK064005 and Bioland Laboratory grants 2018GZR110104001 and 2018GZR110102004. L.L. was supported by NSFC grant 82100785 and China Postdoctoral Science Foundation grant 2021M691471.

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Y.L. conceived the article and provided the outlines of the manuscript. L.L. researched data for the article. L.L. and Y.L. wrote the manuscript. L.L. and H.F. made the figures. All authors made substantial contributions to discussions of the content and edited the manuscript before submission.

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Correspondence to Youhua Liu.

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Nature Reviews Nephrology thanks Christos Chatziantoniou, Hui Yao Lan and Marta Ruiz-Ortega, who co-reviewed with Raul R. Rodrigues-Diez, for their contributions to the peer review of this work.

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Proteolysis: https://www.sciencedirect.com/topics/medicine-and-dentistry/protein-degradation

Glossary

Partial epithelial-to-mesenchymal transition

(Partial EMT). Tubular epithelial cells undergo a process of partial EMT in vivo in which they exhibit some phenotypic changes but stay within the tubular compartment. Partial EMT could be viewed as a transitional stage in which epithelial cells can further regress to cell-cycle arrest and senescence or return to normal epithelia.

Extracellular vesicles

Lipid bilayer-encircled particles that are released from almost all cell types and carry a cargo of proteins, mRNAs, microRNAs, long non-coding RNAs, lipids and metabolites. Extracellular vesicles can mediate cell–cell communication and signal exchange and are thought to have important roles in regulating biological processes including embryogenesis, injury repair and regeneration and the pathogenesis of disease.

Stem cell niche

A specific tissue microenvironment in which stem cells are present in an undifferentiated and self-renewable state.

Kidney tissue scaffolds

(KTS). Decellularized extracellular matrix scaffold derived from normal or diseased kidneys that retains the critical structural, mechanical and physiological properties of renal structures.

Matrikines

Peptides that are liberated by partial proteolysis of extracellular matrix proteins such as collagens, fibronectin, laminins, elastin and matricellular proteins. Matrikines are able to regulate biological processes and often have activities that are different from those of their parent proteins.

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Li, L., Fu, H. & Liu, Y. The fibrogenic niche in kidney fibrosis: components and mechanisms. Nat Rev Nephrol 18, 545–557 (2022). https://doi.org/10.1038/s41581-022-00590-z

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