Kidney injury and progression to chronic kidney disease (CKD) involve metabolic reprogramming of tubular epithelial cells from fatty acid oxidation to glycolysis as a fuel source, and their transition to a senescent, proinflammatory and profibrotic phenotype. Previous work linked WNT–β-catenin signalling to these processes; however, the mechanisms that regulated this signalling pathway were unknown. In a new study, researchers identify WNT10B and FOXO6 as key players in tubular senescence and fibrosis, offering a potential new therapeutic target for CKD interventions.

To identify key WNT family members most closely associated with tubular senescence and kidney fibrosis, Lili Zhou and colleagues performed an intersectional analysis of transcriptome datasets from patients with CKD. That work identified WNT10B — which had previously been linked to natural ageing in the kidney — as a potential candidate. Upregulation of WNT10B in patients with CKD correlated positively with kidney injury and markers of senescence and inflammation, and inversely with estimated glomerular filtration rate. Mouse models of CKD also demonstrated a progressive increase in WNT10B along with tubular senescence.