## 3 Discussion  
This study demonstrates that exogenous IMD significantly protects against contrast media-induced endothelial injury in a rat model of CIAKI. Specifically, IMD reduces PTC damage and overall cellular injury by activating the cAMP/Rac1 signaling pathway, which helps maintain endothelial barrier integrity. CIAKI is a serious iatrogenic complication in clinical practice, but its mechanism has not been fully elucidated due to its complex pathophysiology. Previous studies have focused on the toxic effect of CM on renal tubules, but some studies suggest that renal vascular damage caused by CM and toxic effects on renal tubular cells are the key factors in CIAKI [12; 33]. PTCs, which are the main vessels supplying the renal tubules and interstitium, consist of small straight vessels and cortical PTCs [34; 35]. The small straight medullary vessels are essential for regulating renal medullary blood flow, and renal medullary hypoxia is central to the pathophysiology of CIAKI [36]. Experimental studies have indicated that vascular injury, characterized by impaired endothelial cell function, is a hallmark of CIAKI [12]. When CM enter the body through an artery or vein and directly interacts with vascular endothelial cells, their cytotoxicity can lead to apoptosis or necrosis of these cells, as demonstrated in both in vitro and in vivo studies [36; 37]. CM exposure increases mitochondrial dysfunction and oxygen consumption, resulting in the accumulation of ROS. This ROS accumulation induces endothelial cell apoptosis and inflammation, exacerbating endothelial injury and further contributing to mitochondrial renal dysfunction and parenchymal hypoxia due to endothelial dysfunction and renal tubular transport disorders [38; 39]. Additionally, CM inhibit the production of vasodilators (such as nitric oxide and prostacyclin) while promoting the production of vasoconstretricors (like endothelin) in endothelial cells, leading to PTC vasoconstriction and renal ischemia [40]. Endothelial dysfunction following CM administration also diminishes the anti-inflammatory and antithrombotic properties of blood vessels, increasing the risk of systemic and organ-specific complications [39]. Elevated levels of plasma endothelial cell markers (von Willebrand Factor and tissue-type plasminogen activator) have been observed after CM injection in rats, and CM have been shown to induce the release of circulating endothelial microparticles in patients with cardiovascular disease after angiography [41]. Therefore, improving endothelial dysfunction in PTCs may represent a viable strategy for preventing CIAKI. Endothelial barrier function is regulated by intercellular AJs and TJs [13; 42]. VE-cadherin, the principal component of intercellular adhesion, interacts with the actin cytoskeleton via associated proteins such as \(\alpha\)-catenin and \(\beta\)-catenin. The VE-cadherin-catenin complex is dynamic and disappears from the extracellular space in response to various stimuli, such as thrombin, that reduce endothelial barrier function [43]. Figure 5: IMD protects the PTC endothelial barrier: a representative microphotograph of the ultrastructural changes of peritubular capillary endothelial cells, cell membrane discontinuity (shown by green arrows), and basement membrane fracture (shown by blue arrows) (original magnification, 12,000; scale, 1 \(\upmu\)m). IMD, a member of the CGRP family, shares 28% homology with adrenomedullin [18]. IMD plays a crucial role in regulating homeostasis and maintaining various physiological and pathological functions. It exerts multiple biological effects, including vasodilation, stabilization of the endothelial barrier, and inhibition of cell apoptosis. Similar to adrenomedullin, IMD enhances the production of intracellular cAMP across various systems, including the cardiovascular system, through the calcitonin receptor-like receptor/receptor activity-modifying protein (CLR/RAMP) receptor complexes [44; 45].