Pathophysiology of Kidney Fibrosis

Kidney fibrosis is the final common pathway of chronic kidney diseases, characterised by excessive deposition of extracellular matrix and activation of fibroblasts and myofibroblasts within the interstitium and glomeruli. It follows an initial insult that triggers tubular epithelial injury, maladaptive repair, persistent inflammation and vascular rarefaction. Injured tubular epithelial cells release profibrotic cytokines and undergo partial epithelial-to-mesenchymal transition, while recruited and resident immune cells—principally macrophages—secrete growth factors such as TGF-β and IL-1β to perpetuate fibroblast activation. Myofibroblasts, the principal effector cells, synthesise collagen I and III, leading to parenchymal scarring and progressive loss of renal function. Genetic and epigenetic regulators, including DNA methylation and histone modifications, further modulate fibrogenic gene programmes, offering potential targets to halt or reverse fibrosis.

Research from Nature Portfolio

Recent studies have uncovered the epigenetic regulation of fibrogenesis via histone lysine crotonylation in tubular epithelial cells. Elevated H3K9 crotonylation driven by ACSS2 upregulates IL-1β expression, which in turn activates macrophages and induces tubular cell senescence. Both genetic knockout and pharmacological inhibition of ACSS2 reduce this crotonylation-dependent inflammatory axis, attenuating macrophage–epithelial crosstalk and slowing fibrotic progression, thus nominating ACSS2 as a promising antifibrotic target.

Pathophysiology of Kidney Fibrosis publication trend

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

Technical terms

Extracellular matrix: Network of secreted proteins and polysaccharides that provides structural support and biochemical signals to renal cells.

Myofibroblast: Activated mesenchymal cell that expresses α-smooth muscle actin and produces matrix proteins during fibrogenesis.

Epithelial-to-mesenchymal transition (EMT): Process by which epithelial cells acquire mesenchymal traits, contributing to profibrotic cytokine release and matrix production.

Histone crotonylation: Post-translational modification of histone lysine residues that regulates gene transcription in fibrotic programmes.

ACSS2: Acyl-CoA synthetase short-chain family member 2, an enzyme that generates crotonyl-CoA to drive histone crotonylation in tubular cells.

Vitronectin: Glycoprotein component of the extracellular matrix that mediates cell adhesion and promotes fibroblast activation via integrin signalling.

References

1. Kidney fibrosis: from mechanisms to therapeutic medicines. Signal Transduction and Targeted Therapy (2023).
2. Inhibition of ACSS2-mediated histone crotonylation alleviates kidney fibrosis via IL-1β-dependent macrophage activation and tubular cell senescence. Nature Communications (2024).
3. Macrophage promotes fibroblast activation and kidney fibrosis by assembling a vitronectin-enriched microenvironment. Theranostics (2023).
4. Identification of novel therapeutic targets for chronic kidney disease and kidney function by integrating multi-omics proteome with transcriptome. Genome Medicine (2024).