Society of Diabetic Nephropathy Prevention Journal of Nephropathology 2251-8363 16 1 2027 01 01 Molecular crosstalk in the lung-kidney axis; inflammatory cascades and exosomal signaling pathways mediating renal dysfunction in COVID-19-induced pulmonary injury e28756 e28756 10.34172/jnp.28756 EN Saeed Hosseininia https://orcid.org/0000-0003-4762-5756 Sousan Mohammadi Kebar https://orcid.org/0000-0001-8043-9264 Journal Article 10.34172/jnp.28756 2026 07 19 2026 09 07 COVID-19 primarily manifests as severe pulmonary injury, nevertheless acute kidney injury (AKI) represents a frequent and devastating extrapulmonary complication. The precise mechanisms linking SARS-CoV-2-induced lung damage to renal dysfunction remain incompletely understood, emphasizing the critical importance of the lung-kidney axis. This inter-organ crosstalk is predominantly driven by dysregulated systemic inflammatory cascades and intricate exosomal signaling pathways. Upon severe pulmonary infection, the localized immune response escalates into a systemic cytokine storm, releasing massive quantities of pro-inflammatory mediators such as interleukin-6 and tumor necrosis factor-alpha. This hyperinflammatory state induces widespread endothelial dysfunction, microvascular thrombosis, and direct ischemic damage to renal tubular epithelial cells. Concurrently, recent studies highlight the critical role of exosomes in mediating this distant organ injury. Damaged alveolar epithelial and endothelial cells release lung-derived exosomes packed with damage-associated molecular patterns, viral proteins, and specific microRNAs into the systemic circulation. Upon reaching the kidneys, these extracellular vesicles are internalized by renal cells, where their bioactive payloads dysregulate local transcriptomic profiles, exacerbating oxidative stress, mitochondrial dysfunction, and apoptotic cascades. The synergistic interplay between systemic inflammation and exosomal cargo transfer fundamentally disrupts renal homeostasis, accelerating the progression of AKI. Elucidating the molecular crosstalk within the lung-kidney axis not only clarifies the pathophysiology of multi-organ failure in severe COVID-19 but also identifies circulating exosomal microRNAs as potential diagnostic biomarkers. Furthermore, targeting these specific inflammatory and exosomal signaling pathways offers promising novel therapeutic strategies to preserve renal function and improve overall survival in critically ill patients.