Macrophage-driven inflammation in acute kidney injury: Therapeutic opportunities and challenges

Acute kidney injury (AKI) is increasingly being recognized as a systemic disorder associated with significant morbidity and mortality. AKI manifests with extensive cellular damage, necrosis, and an intense inflammatory response, often leading to late-stage interstitial fibrosis. Although the mechanisms underlying renal injury and repair remain poorly understood, macrophages (pivotal inflammatory cells) play central roles in AKI. They undergo polarization into pro-inflammatory and anti-inflammatory phenotypes, contributing dynamically to both the injury and repair processes while maintaining homeostasis. Macrophages modulate microenvironmental inflammation by releasing extracellular vesicles (EVs) containing pro- or anti-inflammatory signaling molecules, thereby influencing the regulation of tissue injury. The injured tissue cells release EVs and activate local macrophages to initiate these responses. Our bibliometric analysis indicated that a shift has occurred in AKI macrophage research towards therapeutic strategies and clinical translation, focusing on macrophage-targeted therapies, including exosomes and nanoparticles. This review highlights the roles and mechanisms of macrophage activation, phenotypic polarization, and trans-differentiation in AKI and discusses macrophage-based approaches for AKI prevention and treatment. Understanding the involvement of macrophages in AKI contributes to the comprehension of related immune mechanisms and lays the groundwork for novel diagnostic and therapeutic avenues.