Apelin-36 attenuates diabetic glomerular endothelial hyperpermeability via the KLF2/Occludin pathway

An increase in glomerular endothelial cell (GEC) permeability is an early trigger for diabetic nephropathy (DN). This study investigated the protective role of the Apelin-36/APJ axis under diabetic conditions. In vitro, high glucose (HG) downregulated APJ expression and secretion of Apelin-36 in human renal glomerular endothelial cells (HRGECs) in a time-dependent manner and induced endothelial hyperpermeability. Apelin-36 treatment dose-dependently mitigated this hyperpermeability, restored the expression of Occludin and Krüppel-like factor 2 (KLF2) suppressed by HG, and activated the Apelin/APJ system. KLF2 knockdown or pharmacological APJ inhibition abolished the protective effects of Apelin-36. In vivo, Apelin-36 treatment ameliorated albuminuria, restored glomerular Occludin expression, and partially rescued the disrupted Apelin/APJ axis in db/db mice. These findings demonstrate that the Apelin-36/APJ axis protects against glomerular endothelial dysfunction in DN via the KLF2/Occludin pathway, highlighting its potential as a therapeutic target for diabetic renal injury, particularly in the glomerular endothelium.