Impact of soluble Flt-1 on endothelial cell activation and its implications in leukocyte adhesion and microvascular dysfunction in ischemia-reperfusion injury

• Applicant: Privatdozentin Giovana Seno Di Marco, Ph.D.
• Subject Area: Nephrology
• Term: from 2019 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 418505912

Acute kidney disease (AKI) is a common, complex and potentially life-threatening disease. Renal ischemia/reperfusion (IR) injury is a leading cause of ischemic AKI, having as consequence the reduction of the global or local renal blood flow. Activation of endothelial cells and inflammation, thus resulting in disturbance of the renal microcirculation, appear to be a key role for the further processes involved in IR-associated AKI. A possible explanation for the lack of vascular repair is that renal IR results in a shift of expressed factors in favor of anti-angiogenesis vs. angiogenesis/vascular stabilization. We have shown that the soluble vascular endothelial growth factor (VEGF) receptor 1 (known as sFlt-1) is increased in a murine model of IR and throughout the first weeks after renal transplantation (Tx), a unique human/clinical model of IR. By neutralizing VEGF, a crucial cytokine for angiogenesis and endothelial cell maintenance, elevated sFlt-1 levels may contribute to the impairment of endothelial repair, chronically compromising endothelial function and the microvasculature. However, if the role of sFlt-1 in causing endothelial dysfunction is well characterized by us and others, its role in endothelial activation, an important step in leukocyte adhesion and inflammation, is poorly explored. Our preliminary results show that recombinant sFlt-1 increases the adhesiveness of endothelial cells to leukocytes in vitro. In animals, recombinant sFlt-1 delivered by osmotic minipumps induces leukocyte adhesion to cremaster endothelial cells and increases leukocyte transmigration as assessed by intravital microscopy. In addition, it leads to increased leukocyte-endothelial interactions in the kidney; increased expression of proinflammatory mediators and decreased regional blood volume. In other words, it leads to similar endothelial injury as in ischemic AKI. Conversely, in Tx patients, sFlt-1 correlates with markers of endothelial cell activation/dysfunction (sVCAM) and inflammation (C-reactive protein). Moreover, high sFlt-1 levels are associated with decreased capillary density in renal biopsies, and with all outcomes associated with ischemic AKI in these patients, namely delayed graft function, acute rejection, impaired late graft function, and mortality. In this context, we hypothesized that 1) sFlt-1 participates in ischemia/reperfusion injury by contributing to endothelial dysfunction/activation, and, consequently, to leukocyte-endothelial cell adhesion; and that 2) leukocyte adhesion is a possible additional mechanism by which sFlt-1 causes endothelial damage/vessel dropout. In this context, inhibition of sFlt-1 would minimize the IR injury by reducing leukocyte recruitment; and/or improving the capacity to maintain renal microvascular integrity. Understanding the link between sFlt-1 and inflammation may be helpful to unravel sFlt-1 role in IR-associated AKI.

• DFG Programme: Research Grants
• Co-Investigator: Professor Dr. Marcus Brand