Therapeutic targeting of MARCKS for modulating macrophages in kidney injury and fibrosis 4003

Abstract Description Acute kidney injury (AKI), characterized by sudden kidney dysfunction, often progresses to chronic kidney disease (CKD) due to incomplete recovery. Macrophage infiltration and polarization are pivotal in AKI recovery, but their roles in disease progression remain poorly understood. This study identifies MARCKS as a key regulator of macrophage-mediated inflammation and fibrosis in kidney injury. Transcriptomic analyses revealed upregulation of MARCKS in macrophages within injured kidneys. Using primary macrophages, precision-cut kidney slices (PCKS), and cisplatin-exposed mice with macrophage-specific MARCKS deletion, we investigated its functional role. Mice lacking macrophage MARCKS showed improved kidney function, enhanced survival, and reduced fibrosis in models of severe AKI and the AKI-to-CKD transition. PCKS derived from these mice exhibited fewer fibrotic lesions, lower collagen deposition, and reduced pro-fibrotic macrophage infiltration in response to fibrosis inducers. MARCKS deletion disrupted macrophage infiltration, activation, and motility, suppressed PI3K/AKT signaling, and increased apoptosis in co-cultured PCKS. Furthermore, pharmacological inhibition of MARCKS activity reduced serum creatinine and blood urea nitrogen levels, highlighting its therapeutic potential. These findings establish MARCKS as a key driver of kidney fibrosis via macrophage reprogramming and propose its targeting as a promising strategy for managing kidney disease. Funding Sources This work was supported by the NIH grant R01HL146802, the UCOP TRDRP grant T32IR5347, and the DoD PRMRP grant W81XWH2110086 (#PR202411). Topic Categories Immune Mechanisms of Human Disease (HUM)