Abstract: ELABELA (ELA), an endogenous ligand of the apelin receptor (also known as apelin peptide jejunum APJ), has been shown to decrease in the plasma of patients with diabetic kidney disease (DKD). In the current study, we explored the potential function as well as the underlying mechanisms of ELA in DKD. We first found that the ELA levels were decreased in the kidneys of DKD mice. Then, we found that ELA administration mitigated renal damage and downregulated the expression of fibronectin, collagen Ⅳ, and transforming growth factor-β1 in the db/db mice and the high glucose cultured HK-2 cells. Furthermore, the autophagy markers, Beclin-1 and LC3-Ⅱ/LC3-Ⅰ ratio, were significantly impaired in DKD, but the ELA treatment reversed these alterations. Mechanistically, the inhibitory effects of ELA on the secretion of fibrosis-associated proteins in high glucose conditions were blocked by pretreatment with 3-methyladenine (an autophagy inhibitor). In summary, these in vivo and in vitro results demonstrate that ELA effectively protects against DKD by activating high glucose-inhibited renal tubular autophagy, potentially serving as a novel therapeutic candidate for DKD.