Thirty-Eight-Negative Kinase 1 Is a Mediator of Acute Kidney Injury in Experimental and Clinical Traumatic Hemorrhagic Shock

Abstract

Trauma represents a major socioeconomic burden worldwide. After a severe injury, hemorrhagic shock (HS) as a frequent concomitant aspect is a central driver of systemic inflammation and organ damage. The kidney is often strongly affected by traumatic-HS, and acute kidney injury (AKI) poses the patient at great risk for adverse outcome. Recently, thirty-eight-negative kinase 1 (TNK1) was proposed to play a detrimental role in organ damage after trauma/HS. Therefore, we aimed to assess the role of TNK1 in HS-induced kidney injury in a murine and a post hoc analysis of a non-human primate model of HS comparable to the clinical situation. Mice and non-human primates underwent resuscitated HS at 30 mmHg for 60 min. 5 h after the induction of shock, animals were assessed for systemic inflammation and TNK1 expression in the kidney. In vitro, murine distal convoluted tubule cells were stimulated with inflammatory mediators to gain mechanistic insights into the role of TNK1 in kidney dysfunction. In a translational approach, we investigated blood drawn from either healthy volunteers or severely injured patients at different time points after trauma (from arrival at the emergency room and at fixed time intervals until 10 days post injury; identifier: NCT02682550, https://clinicaltrials.gov/ct2/show/NCT02682550). A pronounced inflammatory response, as seen by increased IL-6 plasma levels as well as early signs of AKI, were observed in mice, non-human primates, and humans after trauma/HS. TNK1 was found in the plasma early after trauma-HS in trauma patients. Renal TNK1 expression was significantly increased in mice and non-human primates after HS, and these effects with concomitant induction of apoptosis were blocked by therapeutic inhibition of complement C3 activation in non-human primates. Mechanistically, in vitro data suggested that IL-6 rather than C3 cleavage products

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

“…Once expressed, this kinase exhibits maximum catalytic activity (Armacki et al 2018). TNK1 is moderately expressed in the kidney, and its expression has been shown to be upregulated in several animal models of HS/trauma (Hoehn et al 1996;Halbgebauer et al 2020). Likewise, our study showed that HS induced renal expression of TNK1 in rats, accompanied by the development of kidney injury.…”

“…This gene is originally cloned from CD34 þ /Lin-/CD38-hematopoietic stem/progenitor cells (Hoehn et al 1996). Renal expression of TNK1 is significantly upregulated in experimental HS in mice and non-human primates as well as patients with severe trauma, and closely associated with the severity of inflammation and kidney injury (Halbgebauer et al 2020). It is reported that TNK1 plays an important role in inflammation.…”

Innate immunity and immunotherapy for hemorrhagic shock

“…IL-6 plays a prominent role in the differentiation from Th1 to Th2 in the development of HS ( 67 ). The secretion of IL-6 is positively correlated with the prognosis patients with shock and organ dysfunction ( 68 , 69 ). Zhang Yong et al.…”

Mesenchymal Stem Cells Derived Extracellular Vesicles Alleviate Traumatic Hemorrhagic Shock Induced Hepatic Injury via IL-10/PTPN22-Mediated M2 Kupffer Cell Polarization

“…THS-induced injury is accompanied by immune dysfunction exhibited by excessively inflammasomes release and multiple inflammatory signaling pathways activation. These events lead to an immune-suppressive state and host defense failure, eventually giving rise to inflammation-mediated infection and organ dysfunction ( 2 , 4 ). Therefore, clinical treatments to block immune disorders and prevent organ damage are urgently needed and will have a significant global impact on patient outcomes after THS.…”