Tissular glucocorticoid reactivating enzyme 11β-HSD1 drives pathogenic myofibroblast differentiation in chronic kidney disease

Chronic kidney disease (CKD) is a growing public health crisis, affecting over 10% of the global population and significantly increasing mortality and morbidity. Irrespective of its underlying cause, tubulointerstitial fibrosis (TIF) is a hallmark of CKD progression, with myofibroblasts being the primary effectors of renal fibrosis.

Here, we show that 11beta-hydroxysteroid dehydrogenase type 1 (11β-HSD1) is a critical driver of pathogenic myofibroblast differentiation and fibrosis in CKD. Using genetic deletion and pharmacological inhibition of 11β-HSD1 in mouse models, we demonstrate a marked reduction in TIF severity and improved renal function, linked to the suppression of a regulatory myofibroblast (Reg-MF) subpopulation.

Single-cell and spatial transcriptomics data reveal that 11β-HSD1 is essential for the activation and expansion of Reg-MFs, which is conserved across species and predicts worse outcomes in CKD patients and kidney allograft recipients.

These findings establish a direct link between 11β-HSD1 activity and renal fibrogenesis, highlighting its role during the transition from pericytes to pathogenic Reg-MFs. Our results support 11β-HSD1 inhibition as a promising therapeutic strategy to mitigate CKD progression, offering both mechanistic insights and translational potential for improving patient outcomes.