The Novel Compound SUL-138 Counteracts Endothelial Cell and Kidney Dysfunction in Sepsis by Preserving Mitochondrial Function

• Published in: International journal of molecular sciences 2023-03, Vol.24 (7), p.6330
• Main Authors: Star, Bastiaan S, van der Slikke, Elisabeth C, van Buiten, Azuwerus, Henning, Robert H, Bouma, Hjalmar R
• Format: Article
• Language: English
• Subjects: AKI; Analysis; Animal models; Animals; Apoptosis; Biopsy; Blood; Body temperature; Cecum; E-selectin; Endothelial cells; Endothelial Cells - metabolism; Endothelium; Hypoxia; IL-1β; Infection; Inflammation; Instrument industry; Intercellular adhesion molecule 1; Interleukin 18; Interleukin 6; Interleukin-6 - metabolism; Kidney - metabolism; Kidney diseases; Kidneys; Lipopolysaccharides; Lipopolysaccharides - metabolism; Lipopolysaccharides - toxicity; Membrane potential; Membranes; metabolism; Mice; Mitochondria; Mitochondria - metabolism; Mortality; Multiple Organ Failure - metabolism; Musculoskeletal system; Oxidative stress; Oxygen consumption; Plasma levels; Renal function; Sepsis; Sepsis - complications; Sepsis - drug therapy; Sepsis - metabolism; SUL-138; Tumor Necrosis Factor-alpha - metabolism; Tumor necrosis factor-α
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms24076330

Sepsis is defined as a dysregulated host response leading to organ dysfunction, which may ultimately result in the patient's death. Mitochondrial dysfunction plays a key role in developing organ dysfunction in sepsis. In this study, we explored the efficacy of the novel mitochondrial protective compound, SUL-138, in sepsis models in HUVECs and mice. In LPS-challenged HUVECs, SUL-138 preserved mitochondrial membrane potential and oxygen consumption and limited mitochondrial oxidative stress, resulting in increased survival at 48 h. Further, SUL-138 dampened the LPS-induced expression of IL-1β, but not of NLRP3, and IL-18 in HUVECs. Sepsis in mice induced by cecal ligation and puncture (CLP) led to a lower mitochondrial membrane potential and increased levels of mitochondrial oxidative stress in the kidney, which SUL-138 limited. In addition, SUL-138 mitigated the CLP-induced increase in kidney dysfunction markers NGAL and urea. It dampened the rise in kidney expression of IL-6, IL-1β, and ICAM-1, but not TNF-α and E-selectin. Yet, SUL-138 limited the increase in plasma levels of IL-6 and TNF-α of CLP mice. These results demonstrate that SUL-138 supports mitochondrial function, resulting in a limitation of systemic inflammation and preservation of kidney function.