Surfactant protein A (SP-A) alleviates acute kidney injury by reducing macrophage recruitment and M1 polarization

Acute kidney injury (AKI) is a severe clinical condition characterized by rapid renal function decline and intense intrarenal inflammation. Surfactant Protein A (SP-A), known for its pulmonary immunomodulatory roles, is investigated here for its therapeutic potential in AKI recovery. Using a male C57BL/6J mouse model of bilateral renal pedicle clamping, we demonstrate that an SP-A agonist significantly preserves renal function, reducing serum creatinine and urea nitrogen levels, and attenuates histopathological tissue damage. Mechanistically, SP-A activation suppresses the infiltration of CD11b⁺F4/80⁺ macrophage, while shifting polarization by decreasing the proportion of F4/80⁺iNOS⁺ M1 cells and increasing that of F4/80⁺CD206⁺ M2 cells both in vivo and in vitro. In lipopolysaccharide (LPS)-stimulated RAW 264.7 cells, SP-A knockdown increases the secretion of TNF-α, IL-6, and IL-1β, and enhances cell migration ability, whereas SP-A treatment reverses these effects. These actions are mediated via inhibiting the NF-κB signaling pathway. Clodronate liposome-mediated macrophage depletion demonstrates that SP-A exerts its therapeutic effects, to some extent, through the mediation of macrophage. Co-culture of SP-A-pretreated RAW 264.7 cells with HK-2 cells revealed that SP-A-treated RAW 264.7 cells inhibit Kim-1 expression, and increase IGF-1 expression. Collectively, these findings reveal that SP-A reduces macrophage recruitment, suppresses M1 macrophage polarization, alleviates inflammation, and ameliorates AKI via the NF-κB pathway, offering a promising therapeutic target for AKI.