Mechanisms and Modulation of Kidney Fibrosis

Kidney fibrosis represents the final common pathway of chronic renal injury and is defined by persistent activation of stromal cells and excessive deposition of connective tissue. Resident fibroblasts, pericytes and endothelial cells undergo phenotypic conversion into contractile myofibroblasts under the influence of key cytokines such as transforming growth factor-β (TGF-β) and platelet-derived growth factor (PDGF). This process is modulated by post-translational events—including core fucosylation of surface receptors—and by transcriptional programmes orchestrated by factors like MRTF-A, ZEB1 and IRF9. Concurrently, epithelial-to-mesenchymal and endothelial-to-mesenchymal transitions expand the profibrotic cell pool, while interactions with specialised macrophage subsets amplify extracellular matrix (ECM) accumulation. Emerging therapeutic strategies aim to disrupt these molecular circuits through enzymatic inhibitors, peptide mimetics and targeted small molecules. In parallel, advanced bioengineered models facilitate high-throughput drug screening, offering a translational bridge towards preserving renal structure and function.

Research from Nature Portfolio

Foundational studies have elucidated the role of glycosylation in pericyte-to-myofibroblast transition, demonstrating that inhibition of fucosyltransferase-mediated core fucosylation impairs TGF-β and PDGF receptor activation, thereby reducing interstitial matrix deposition and preserving renal architecture. Complementary work has unveiled protein phosphatase 2A (PP2A) as a key facilitator of endothelial-to-mesenchymal transition. A peptide-based inhibitor that prevents nitration-dependent activation of PP2A has been shown to maintain endothelial integrity, limit mesenchymal conversion and attenuate fibrosis in obstructive nephropathy models. Together, these findings position enzymatic modification of receptor and phosphatase function as central modulators of fibrogenic signalling cascades.

Mechanisms and Modulation of Kidney Fibrosis publication trend

The graph below shows the total number of articles in mechanisms and modulation of kidney fibrosis across all publications each year (not limited to Nature Index journals).

Technical terms

Myofibroblast: specialised contractile cell derived from fibroblast or pericyte lineages that secretes extracellular matrix proteins during repair and fibrosis.

Pericyte: perivascular support cell capable of detaching and differentiating into matrix-producing myofibroblasts following injury.

Endothelial-to-mesenchymal transition (EndMT): process whereby endothelial cells acquire mesenchymal features, contributing to the pool of fibrogenic cells.

Core fucosylation: enzymatic addition of fucose residues to N-linked glycans on receptors, modulating downstream signalling.

Protein phosphatase 2A (PP2A): serine/threonine phosphatase that, when activated, drives EndMT and fibrotic remodelling.

Extracellular matrix (ECM): network of fibrous proteins and glycoproteins that accumulates aberrantly in fibrotic tissues.

References

1. An MRTF-A–ZEB1–IRF9 axis contributes to fibroblast–myofibroblast transition and renal fibrosis. Experimental & Molecular Medicine (2023).
2. Meis1 Targets Protein Tyrosine Phosphatase Receptor J in Fibroblast to Retard Chronic Kidney Disease Progression. Advanced Science (2024).
3. A bioprinted and scalable model of human tubulo-interstitial kidney fibrosis. Biomaterials (2024).
4. Platelet-instructed SPP1+ macrophages drive myofibroblast activation in fibrosis in a CXCL4-dependent manner. Cell Reports (2023).
5. Novel Mechanism of the Pericyte-Myofibroblast Transition in Renal Interstitial Fibrosis: Core Fucosylation Regulation. Scientific Reports (2017).
6. Blocking protein phosphatase 2A signaling prevents endothelial-to-mesenchymal transition and renal fibrosis: a peptide-based drug therapy. Scientific Reports (2016).