Role of Sema7A during the Resolution of Kidney Ischemia-/Reperfusion Injury

• Applicant: Dr. Andreas Körner
• Subject Area: Nephrology ; Anaesthesiology
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 493804599

Various clinical conditions such as tissue resection, transplant surgery, or hemorrhagic shock are critical causes of renal dysfunction or failure. Ischemia/reperfusion (I/R) injury is the major cause of renal injury in these events and contributes to significant morbidity and mortality. A hallmark of the development of renal I/R damage is the recruitment of activated neutrophils to the affected tissue. This process is controlled by endogenous signals, mostly cytokines and chemokines, that control the extent of leukocyte infiltration into the kidney. Prompt elimination of apoptotic leukocytes is essential for the return of the affected tissue to homeostasis and for complete resolution of inflammation. This resolution of inflammation is an active process that ideally leads to restored organ function. Hallmarks of this phase include downregulation of proinflammatory gene expression, reduction of leukocyte activation, and clearance of inflammatory cells through efferocytosis. In addition to the resolution of inflammation, renal tissue regeneration after I/R injury is strongly associated with patient outcome. Recent work has found that neuronal guidance molecules, originally identified in the nervous system, have an additional function in the immune system in leukocyte migration and control of acute inflammation. Semaphorin 7A (SEMNA7A) is one of these proteins and in previous work I have demonstrated its influence on the initiation of acute inflammation. This idea, in conjunction with its immunomodulatory effects, led me to ask whether SEMA7A could evoke local resolution programs and promote tissue repair and regeneration during renal I/R injury. In pilot experiments, I found that SEMA7A is actively involved in renal injury by controlling leukocyte infiltration, modifying pro-inflammatory cytokine production, and contributing to phagocytosis of apoptotic polymorphonuclear neutrophils (PMNs). Therefore, here I would like to investigate the effect of SEMA7A on the metabolism of specialized lipid mediators, the degree of PMN apoptosis, the process of efferocytosis, and the impact on renal function. Further understanding of the link between the neuronal guidance protein system and renal inflammation will open new therapeutic options for the future.

• DFG Programme: Independent Junior Research Groups