Fibroblast-derived neuropilin 1 alleviates renal fibrosis progression.

Chronic kidney disease (CKD) is a major global health challenge affecting over 10% of the adult population. A hallmark of CKD progression is the transdifferentiation of kidney fibroblasts into extracellular matrix-producing myofibroblasts, a key mechanism involved in the decline of kidney function and the development of kidney failure. Fibroblasts maintain the structural integrity of the kidney and support epithelial survival, repair, and regeneration after acute kidney injury. Maladaptive repair is a failure to resolve fibroblast activation, which ultimately progresses to chronic injury and CKD. In this study, we showed that the membrane-bound coreceptor neuropilin 1 (NRP1) was essential to maintain fibroblast function and prevent their transdifferentiation into myofibroblasts. We used the myelin protein zero-Cre (P0-Cre) to specifically abrogate Nrp1 in kidney resident fibroblasts during fibrosis progression. We employed kidney-induced interstitial fibrosis models combined with a lineage-tracing strategy, single-cell RNA sequencing analysis, and ex vivo explant cultures to reveal a cell autonomous protective role for NRP1 in limiting fibrosis. Furthermore, we extended the analysis by showing that Nrp1 conditional mutants were more prone to develop cardiac fibrosis in a mouse model of heart failure. Collectively, these findings provide new insights into the signalling pathways controlling the transition from acute to chronic kidney disease conversion and identify NRP1 as a novel regulator of fibroblast supportive function. © 2025 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.