Targeting fibroblast activation protein-α to treat renal fibrosis

Renal fibrosis is the common outcome of chronic renal disease. Currently, there are no effective therapies. Fibroblast activation and extracellular matrix accumulation are key processes driving renal fibrosis. Fibroblast activation protein (FAP) is highly induced in injured kidneys, and immunofluorescence staining revealed that FAP is mainly expressed in Platelet-derived growth factor receptor-beta (PDGFRβ)+ and alpha-smooth muscle actin (α-SMA)+ myofibroblasts in kidney samples from mice with renal fibrosis and patients with chronic kidney diseases or post-acute kidney injury. In this study, targeting FAP as a strategy for treating renal fibrosis is tested using two preclinical animal models: the mouse models of unilateral ureteral obstruction and unilateral renal ischemia–reperfusion. Adoptive transfer of T cells expressing chimeric antigen receptor specific to FAP or administration of an FAP inhibitor (SP-13786) significantly alleviated kidney fibrosis in both mouse models. Eliminating FAP+ fibroblasts using chimeric antigen receptor T-cell (CAR-T) therapy or inhibiting the FAP prevented fibroblast overactivation, proliferation, and migration, promoted apoptosis, and effectively suppressed other myofibroblast populations. Overall, we report herein that targeting FAP offers a novel promising treatment approach for renal fibrosis.