Macrophage-derived FKBP5 exacerbates myocardial injury post-infarction in chronic kidney disease via the HSP90/HIF-1α signaling pathway

Introduction Chronic kidney disease (CKD) is a frequent and lethal comorbidity in patients with acute myocardial infarction (AMI). This study aimed to quantify the clinical impact of CKD on post-MI outcomes and investigate the molecular mechanisms of cardiorenal crosstalk involving FKBP5. Methods We analyzed MI populations from two large-scale cohorts: the CIN-II (n=27,103 MI patients) and the UK Biobank (n=10,809 MI patients). Experimental CKD+MI models were established in mice using 5/6 nephrectomy followed by LAD ligation. Comprehensive flow cytometry was performed across multiple tissues (heart, bone marrow, spleen, peripheral blood) to profile diverse immune cells. Furthermore, transcriptomic sequencing of CKD mouse hearts, cross-referenced with public databases, was utilized to screen for differentially expressed genes. Protein expression and localization were validated via Western blot, PCR, and immunofluorescence (IF). Mechanistically, protein-protein interactions were confirmed using Co-Immunoprecipitation (Co-IP). The in vivo role of FKBP5 in cardiomyocyte apoptosis and remodeling was evaluated using TUNEL staining and the specific inhibitor SAFit2. Results In the CIN-II cohort, 21.03% of AMI patients had comorbid CKD. Compared to those without CKD, CKD+AMI patients showed a 90% increased risk of all-cause mortality and a 139% increased risk of cardiovascular death (validated in UKB). Clinically, CKD was associated with adverse cardiac remodeling. Systematic flow cytometric screening revealed no significant differences in most immune cell types across tissues, except for a specific expansion of CCR2+ macrophages exclusively in CKD+MI hearts. Transcriptomics and protein validation identified FKBP5 as a key upregulated factor, primarily co-localizing with CCR2+ macrophages. Co-IP confirmed that FKBP5 directly interacts with HSP90 in cardiomyocytes, negatively regulating the protective HIF-1α pathway and promoting hypoxia-induced apoptosis. Pharmacological inhibition of FKBP5 by SAFit2 significantly reduced cardiomyocyte apoptosis (via TUNEL assay), decreased infarct size, and improved cardiac function. Conclusion CKD aggravates post-MI cardiac damage by inducing CCR2+ macrophage-derived FKBP5, which suppresses the HSP90/HIF-1α protective axis. Targeting the FKBP5/HSP90 interaction represents a novel therapeutic strategy for cardiorenal syndrome.