HMGB1/MYH9 suppresses PPARγ to induce lung injury in renal ischemia-reperfusion: protective effects of Rosiglitazone.

Abstract

The co-occurrence of acute kidney injury (AKI) and acute lung injury (ALI) is strongly associated with increased mortality. Understanding the role of high mobility group box 1 (HMGB1) in AKI-induced ALI is essential for identifying effective biomarkers and therapeutic targets. We investigated the regulatory mechanism of HMGB1 and myosin heavy chain 9 (MYH9), as well as the effects of Rosiglitazone, a PPARγ agonist, in AKI-induced ALI using C57BL/6J mouse models of renal ischemia-reperfusion injury (IRI) and a renal-lung cell co-culture system. Following renal IRI, elevated serum HMGB1 interacted with lung MYH9, thereby inhibiting PPARγ-a key regulator of inflammation and endothelial barrier integrity-leading to increased levels of CCL2 and impaired endothelial barrier integrity, which ultimately resulted in ALI. Pretreatment with Rosiglitazone restored PPARγ function, reduced inflammation, and alleviated kidney and lung damage. Its therapeutic efficacy in mice was correlated with serum CCL2 levels. Furthermore, in a cohort of 421 critically ill children, higher urinary CCL2 levels were strongly associated with an increased risk of AKI/ALI and poorer survival outcomes. These findings underscore Rosiglitazone's therapeutic potential in AKI-induced ALI and highlight urinary CCL2 as a promising biomarker for treatment monitoring and outcome prediction in pediatric patients. HMGB1 released following renal ischemia-reperfusion binds MYH9 in lungs, suppressing PPARγ, driving inflammation and endothelial barrier dysfunction, thereby contributing to ALI pathogenesis. Rosiglitazone, a PPARγ agonist, restores PPARγ activity, strengthens barriers, reduces inflammation, and mitigates AKI-induced ALI in mouse models, with efficacy tied to serum CCL2 levels. Clinically, elevated urinary CCL2 in critically ill children associates with higher risk of concurrent AKI/ALI and poorer prognosis, indicating CCL2 as a biomarker for treatment response and prognosis. This work highlights a central pathogenic mechanism in AKI-ALI and proposes Rosiglitazone as a potential preventive/therapeutic strategy, with CCL2 guiding clinical monitoring.