Recombinant Klotho Protein Protects Tissues by Mitigating the Detrimental Effects of Sterile Inflammation After...

Hemorrhagic shock (HS) is a life-threatening condition characterized by systemic hypoperfusion, which induces inflammatory responses, oxidative stress, and apoptosis, often leading to multiple organ failure. Klotho, an antiaging protein with anti-inflammatory, antiapoptotic, and antioxidative properties, has demonstrated therapeutic potential in chronic diseases. However, its efficacy in acute conditions, such as HS, remains unexplored.

This study investigated the protective effects of recombinant klotho protein (rKL) on the lungs and kidneys after HS and elucidated the underlying mechanisms.

Adult male Wistar rats were subjected to controlled HS, followed by resuscitation. The animals were divided into four groups: sham, sham + rKL, HS, and HS + rKL. Histopathological analysis, terminal deoxynucleotidyl transferase-mediated 2'-deoxyuridine 5'-triphosphate nick end labeling assay, reactive oxygen species (ROS) staining, enzyme-linked immunosorbent assay, real-time polymerase chain reaction, cytokine array, immunofluorescence staining for M1 and M2 macrophage markers, and high mobility group box-1 protein were performed to evaluate inflammation, apoptosis, and macrophage polarization.

rKL administration markedly attenuated histological tissue damage in the lungs and kidneys, reduced lactate levels, and suppressed apoptosis and ROS accumulation. Furthermore, rKL inhibited the extracellular release of high mobility group box-1 protein and decreased the expression of proinflammatory cytokines. rKL also reduced macrophage infiltration and M1 polarization while increasing the M2/M1 ratio, indicating enhanced resolution of inflammation.

rKL attenuates tissue injury after HS by reducing ROS, apoptosis, and inflammation, as well as modulating macrophage polarization. These findings suggest that rKL may serve as a promising adjunctive therapeutic strategy for improving HS outcomes.