<p>Chronic kidney disease (CKD) is characterized not only by progressive fibrosis but also by systemic endothelial dysfunction and inflammation. Platelets, traditionally recognized for their role in hemostasis, also serve as key modulators of endothelial activation and immune cell recruitment. Platelet activation is commonly observed in patients with CKD and contributes to the proinflammatory environment. Although platelet-endothelial interactions are well-characterized in cardiovascular disease, their role in renal endothelial dysfunction and inflammation remains poorly understood. To investigate this, we used the unilateral ureteral obstruction (UUO) model in mice, to examine how platelet activation influences endothelial responses and monocyte/macrophage recruitment in the early phase of renal fibrosis development. Platelet depletion reduced the number of infiltrating macrophages in kidney tissue, decreased expression of endothelial activation and inflammation markers, and preserved the peritubular capillary (PTC) integrity. Further in vitro studies using human umbilical vein endothelial cells (HUVECs) showed that activated platelets induced endothelial dysfunction and inflammation, in line with the in vivo findings. To recapitulate the vascular microenvironment, we performed a shear flow-based transmigration assay. Monocyte adhesion and transendothelial migration significantly increased when endothelial cells were pretreated with activated platelets compared to unstimulated controls. Moreover, the presence of platelets on the inflamed endothelium further enhanced monocyte migration, suggesting a synergistic effect in promoting immune cell recruitment. Collectively, our findings highlight that activated platelets contribute to endothelial dysfunction, inflammation, and monocyte infiltration in early kidney injury, suggesting their potential as a therapeutic target to mitigate microvascular injury and preserve renal vascular integrity in kidney disease.</p>