Wnt/β-Catenin Signaling in Renal Pathophysiology

Wnt/β-catenin is an evolutionarily conserved pathway governing cell fate, proliferation and survival. In the kidney, canonical Wnt ligands bind Frizzled receptors, inhibiting the β-catenin destruction complex and promoting β-catenin stabilisation. Stabilised β-catenin translocates to the nucleus, where it co-activates transcription of genes involved in repair and regeneration. Under physiological conditions this pathway supports nephron development and tubular recovery after injury. However, sustained or aberrant activation contributes to maladaptive processes—interstitial fibrosis, podocyte dysfunction and epithelial–mesenchymal transition (EMT). Crosstalk with the renin–angiotensin system, inflammatory mediators and metabolic regulators further amplifies profibrotic programmes and mitochondrial impairment. The dualistic role of Wnt/β-catenin in both renal repair and progressive scarring underscores its importance as a therapeutic target in chronic kidney disease and acute kidney injury.

Research from Nature Portfolio

Recent studies have elucidated post-translational control of β-catenin stability via palmitoylation. In fibrotic kidneys, reduced expression of the palmitoyltransferase DHHC9 diminishes β-catenin palmitoylation, leading to impaired ubiquitination and excessive nuclear accumulation. By contrast, acyl protein thioesterase 1 (APT1) removes palmitate from β-catenin, increasing its abundance and transcriptional activity. Modulating this lipid-modification axis—through DHHC9 overexpression or APT1 inhibition—markedly attenuates tubular fibrosis in mouse models, revealing novel entry points for antifibrotic intervention.

Wnt/β-Catenin Signaling in Renal Pathophysiology publication trend

The graph below shows the total number of articles in wnt/β-catenin signaling in renal pathophysiology across all publications each year (not limited to Nature Index journals).

Technical terms

Wnt proteins: A family of secreted glycoproteins that initiate β-catenin stabilisation by binding Frizzled receptors.

β-Catenin: An intracellular signal transducer that, when stabilised, enters the nucleus to regulate gene transcription.

Palmitoylation: A reversible post-translational lipid modification that influences protein stability and localisation.

Ubiquitination: The covalent attachment of ubiquitin moieties to proteins, typically marking them for proteasomal degradation.

Renal fibrosis: The excessive deposition of extracellular matrix and activation of myofibroblasts, leading to kidney scarring and functional decline.

References

1. Palmitoyltransferase DHHC9 and acyl protein thioesterase APT1 modulate renal fibrosis through regulating β-catenin palmitoylation. Nature Communications (2023).
2. Wnt/β‐catenin/RAS signaling mediates age‐related renal fibrosis and is associated with mitochondrial dysfunction. Aging Cell (2019).
3. Plasminogen Activator Inhibitor-1 Is a Transcriptional Target of the Canonical Pathway of Wnt/β-Catenin Signaling*. Journal of Biological Chemistry (2010).
4. Matrix Metalloproteinases-7 and Kidney Fibrosis. Frontiers in Physiology (2017).
5. Targeting the Wnt/β-Catenin Signaling Pathway as a Potential Therapeutic Strategy in Renal Tubulointerstitial Fibrosis. Frontiers in Pharmacology (2021).
6. Cellular Senescence in Kidney Fibrosis: Pathologic Significance and Therapeutic Strategies. Frontiers in Pharmacology (2020).
7. Secreted Frizzled-related Protein 1 (Sfrp1) Regulates the Progression of Renal Fibrosis in a Mouse Model of Obstructive Nephropathy*. Journal of Biological Chemistry (2014).