Attenuation of renal fibrosis in mice due to lack of bombesin receptor‐activated protein homologue

Abstract

AbstractBombesin receptor‐activated protein (BRAP), encoded by the C6orf89 gene in humans, is expressed in various cells with undefined functions. BC004004, the mouse homologue of C6orf89, has been shown to play a role in bleomycin‐induced pulmonary fibrosis through the use of a BC004004 gene knockout mouse (BC004004−/−). In this study, we investigated the potential involvement of BRAP in renal fibrosis using two mouse models: unilateral ureteral obstruction (UUO) and type 2 diabetes mellitus induced by combination of a high‐fat diet (HFD) and streptozocin (STZ). BRAP or its homologue was expressed in tubular epithelial cells (TECs) in the kidneys of patients with chronic kidney disease (CKD) and in BC004004+/+ mice. Compared to control mice, BC004004−/− mice exhibited attenuated renal injury and renal fibrosis after UUO or after HFD/STZ treatment. Immunohistochemistry and immunoblot analyses of the kidneys of BC004004+/+ mice after UUO surgery showed a more significant decrease in E‐cadherin expression and a more significant increase in both α smooth muscle actin (α‐SMA) and vimentin expression compared to BC004004−/− mice. Additionally, stimulation with transforming growth factor‐β1 (TGF‐β1) led to a more significant decrease in E‐cadherin expression and a more significant increase in α‐SMA and vimentin expression in isolated TECs from BC004004+/+ than in those from BC004004−/− mice. These results suggest that an enhanced epithelial‐mesenchymal transition (EMT) process occurred in TECs in BC004004+/+ mice during renal injury, which might contribute to renal fibrosis. The loss of the BRAP homologue in BC004004−/− mice suppressed EMT activation in kidneys and contributed to the suppression of fibrosis during renal injury.