GDF5 exacerbates tubulointerstitial injury by inducing partial epithelial-mesenchymal transition of tubular epithelial cells in diabetic kidney disease

Adipokines serve crucial functions in diabetic kidney disease (DKD) pathogenesis. Growth differentiation factor 5 (GDF5) is highly expressed in adipose tissue, but its specific role in DKD is unknown. In this study, we observed elevated GDF5 expression in both DKD patients and db/db mice, suggesting a potential association between GDF5 and DKD progression. Elevated plasma GDF5 levels are associated with an increased risk of incident CKD in patients with type 2 diabetes mellitus. In animal studies, adipose-specific overexpression of GDF5 increased circulating GDF5 and exacerbated renal injury in db/db mice, characterized by increased tubulointerstitial injury and inflammation infiltration. Conversely, adipose-specific knockdown reduced circulating GDF5 and alleviated renal injury. In vitro studies demonstrated that GDF5 induces partial epithelial-mesenchymal transition (pEMT) in renal tubular epithelial cells via activation of the SMAD1/5/8 signaling pathway, as evidenced by reduced E-cadherin expression and increased Snail1 levels. Notably, the supernatant from GDF5-treated injured HK-2 cells was found to enhance the secretion of pro-inflammatory cytokines by macrophages. These findings suggest that adipose-derived GDF5 acts as a novel mediator contributing to tubulointerstitial injury in DKD.