Tyrosine kinase nonreceptor 1 (TNK1) knockdown ameliorates hemorrhage shock-induced kidney injury via inhibiting macrophage M1 polarization

Abstract

Hemorrhage shock (HS) is a major threat to patients with trauma and spontaneous bleeding, resulting in multi-organ failure including the kidney. Tyrosine kinase nonreceptor 1 (TNK1) has been shown to be upregulated in the kidney of experimental HS and patients with severe trauma. The study aims to investigate the role of TNK1 and the underlying mechanism in HS-induced kidney injury. A model of HS was established with femoral artery bloodletting, followed by resuscitation in Sprague-Dawley rats. Renal expression of TNK1 was abnormally induced by HS in rats. Knockdown of TNK1 alleviated HS-induced cell apoptosis and the level of proinflammatory cytokines (TNF-α, IL-6 and IL-1β) in the kidney. The expression of M1 macrophage markers (CD86 and iNOS) and the activation of STAT1 were inhibited by TNK1 knockdown in HS rats. In vitro, human monocyte THP-1 cells were treated with 20 ng/mL interferon-gamma plus 100 ng/mL lipopolysaccharide to induce M1 polarization. TNK1 knockdown exerted inhibitory effect on macrophage M1 polarization, M1-type inflammatory cytokine production and STAT1 activation in THP-1 cells. In conclusion, downregulation of TNK1 alleviates HS-induced kidney injury by suppressing macrophage M1 polarization, inflammation and kidney cell apoptosis, in which the deactivation of STAT1 signaling may be involved.

Impaired Glucocorticoid Receptor Signaling Aggravates Lung Injury after Hemorrhagic Shock

“…Moreover, we found enhanced levels of the pro-inflammatory iNOS in lung tissue of GR dim/dim mice compared to GR +/+ after HS ( Figure 4 d). HS was shown to increase iNOS in the lungs [ 38 ] and kidneys [ 39 ] of rats. In the kidneys, HS-induced iNOS coincided with increased pSTAT1 levels [ 39 ].…”

“…HS was shown to increase iNOS in the lungs [ 38 ] and kidneys [ 39 ] of rats. In the kidneys, HS-induced iNOS coincided with increased pSTAT1 levels [ 39 ]. Increased iNOS levels in the lungs are associated with aggravated lung damage after HS [ 38 , 40 ] and during lung inflammation, reduced lung compliance was shown to depend on the pro-inflammatory protein iNOS [ 41 ].…”