GOLPH3 promotes endotoxemia-induced liver and kidney injury through Golgi stress-mediated apoptosis and inflammatory response

Abstract

Sepsis is a serious clinical condition characterized by a systemic inflammatory response, a leading cause of acute liver and kidney injury, and is associated with a high morbidity and mortality. Understanding the molecular mechanisms underlying the acute liver and kidney injury is crucial for developing an effective therapy. Golgi apparatus plays important roles and has various substrates mediating cellular stress responses. Golgi phosphoprotein 3 (GOLPH3), linking Golgi membranes to the cytoskeleton, has been identified as an important oncogenic regulator; however, its role in endotoxemia-induced acute liver and kidney injury remains elusive. Here, we found that upregulation of GOLPH3 was associated with endotoxemia-induced acute liver and kidney injury. Lipopolysaccharide (LPS) treatment increased Golgi stress and fragmentation, and associated pro-inflammatory mediator (Tnfα, IL-6, and IL-1β) production in vivo and in vitro. Interestingly, the downregulation of GOLPH3 significantly decreased LPS-induced Golgi stress and pro-inflammatory mediators (Tnfα, IL-6, Mcp1, and Nos2), and reversed apoptotic cell deaths in LPS-treated hepatocytes and renal tubular cells. GOLPH3 knockdown also reduced inflammatory response in LPS-treated macrophages. The AKT/NF-kB signaling pathway was suppressed in GOLPH3 knockdown, which may be associated with a reduction of inflammatory response and apoptosis and the recovery of Golgi morphology and function. Taken together, GOLPH3 plays a crucial role in the development and progression of acute liver and kidney injury by promoting Golgi stress and increasing inflammatory response and apoptosis, suggesting GOLPH3 as a potential therapeutic target for endotoxemia-induced tissue injury.

Galgravin Isolated from Piper kadsura Ameliorates Lipopolysaccharide (LPS)-Induced Endotoxemia in Mice

“…Because the lung, liver, and kidney are vital organs susceptible to LPS toxicity in mice [27], we further examined whether the intraperitoneal administration of galgravin attenuates LPS-induced histological changes in these organs of LPS-challenged mice. We found that galgravin improved hilum congestion, reduced alveolar septal thickening, and significantly diminished alveolar hemorrhage in the lung tissues of LPS-challenged mice (Figure 5A-C,G).…”

The Role of Interferon-Induced Proteins with Tetratricopeptide Repeats 1 and 2 in Sepsis-Induced Acute Liver Injury

“… 6 , 7 Changes in gene and protein expression and functional abnormalities are common events during the sepsis-mediated progression of ALI. 8 , 9 In spite of the rapid research advances, the pathophysiology of sepsis-induced ALI and the interventions to cure ALI are still limited. Hence, it is imperative to comprehensively investigate the underlying mechanisms of sepsis-induced acute liver injury (SALI) and explore the potential therapeutic strategies.…”