Targeting ROS and cPLA2/COX2 Expressions Ameliorated Renal Damage in Obese Mice with Endotoxemia

Abstract

Obesity is associated with metabolic endotoxemia, reactive oxygen species (ROS), chronic inflammation, and obese kidney fibrosis. Although the fat–intestine–kidney axis has been documented, the pathomechanism and therapeutic targets of obese kidney fibrosis remain unelucidated. To mimic obese humans with metabolic endotoxemia, high-fat-diet-fed mice (HF group) were injected with lipopolysaccharide (LPS) to yield the obese kidney fibrosis–metabolic endotoxemia mouse model (HL group). Therapeutic effects of ROS, cytosolic phospholipases A2 (cPLA2) and cyclooxygenase-2 (COX-2) inhibitors were analyzed with a quantitative comparison of immunohistochemistry stains and morphometric approach in the tubulointerstitium of different groups. Compared with basal and HF groups, the HL group exhibited the most prominent obese kidney fibrosis, tubular epithelial lipid vacuoles, and lymphocyte infiltration in the tubulointerstitium. Furthermore, inhibitors of nonspecific ROS, cPLA2 and COX-2 ameliorated the above renal damages. Notably, the ROS-inhibitor-treated group ameliorated not only oxidative injury but also the expression of cPLA2 and COX-2, indicating that ROS functions as the upstream signaling molecule in the inflammatory cascade of obese kidney fibrosis. ROS acts as a key messenger in the signaling transduction of obese kidney fibrosis, activating downstream cPLA2 and COX-2. The given antioxidant treatment ameliorates obese kidney fibrosis resulting from a combined high-fat diet and LPS—ROS could serve as a potential therapeutic target of obese kidney fibrosis with metabolic endotoxemia.

Activation of the VEGF-A/ERK/PLA2 Axis Mediates Early Retinal Endothelial Cell Damage Induced by High Glucose: New Insight from an In Vitro Model of Diabetic Retinopathy

“…Phospholipase A2 (PLA2) plays an important role in cellular injury as it mediates inflammatory processes through the mobilization of arachidonic acid from membrane phospholipids [ 9 , 10 , 11 ]. Increased hydrolysis of membrane phospholipids by PLA2 has been related to an increased permeability of plasma membrane, ROS-induced damage, and apoptosis in response to pro-inflammatory stimuli [ 12 , 13 , 14 , 15 ]. PLA2 is activated in an in vivo model of diabetic retinopathy, involving glucose-induced injury and death of retinal pericytes and endothelium, with subsequent breakdown of the blood–retinal barrier [ 16 ].…”

Kidney Inflammation, Injury and Regeneration

“…Therefore, the development of novel therapies to improve renal regeneration capacity after AKI, to preserve renal function, and to prevent AKI is urgently needed. In this context, we wanted to offer a forum for the publication of new results on renal inflammation, injury and regeneration, as well as for the review and discussion of existing studies from this interesting research field.This Special Issue covers research articles that investigated the molecular mechanisms of inflammation [1-3] and injury [4,5] during different renal pathologies and renal regeneration [6], diagnostics using new biomarkers [7-9], and the effects of different stimuli like medication or bacterial components on isolated renal cells or in vivo models [10][11][12], all of which were summarized in a very simplified manner. Furthermore, this Special Issue contains important reviews that dealt with the current knowledge of cell death and regeneration [13,14], inflammation [15][16][17][18], and the molecular mechanisms of kidney diseases [19][20][21][22].…”

“…This Special Issue covers research articles that investigated the molecular mechanisms of inflammation [1][2][3] and injury [4,5] during different renal pathologies and renal regeneration [6], diagnostics using new biomarkers [7][8][9], and the effects of different stimuli like medication or bacterial components on isolated renal cells or in vivo models [10][11][12], all of which were summarized in a very simplified manner. Furthermore, this Special Issue contains important reviews that dealt with the current knowledge of cell death and regeneration [13,14], inflammation [15][16][17][18], and the molecular mechanisms of kidney diseases [19][20][21][22].…”

“…No injury or inflammatory effects of two anti-diabetically used gliflozins on proximal tubular epithelial cells that were cultured in hyperglycemic conditions were found [10]. Stimulations with bacterial lipopolysaccharide were used to investigate acute renal fibrosis in a model of sepsis-induced AKI [11] and the inflammatory cascade of obese kidney fibrosis in a metabolic endotoxemia mouse model [12].…”

Therapeutic Targeting of Aristolochic Acid Induced Uremic Toxin Retention, SMAD 2/3 and JNK/ERK Pathways in Tubulointerstitial Fibrosis: Nephroprotective Role of Propolis in Chronic Kidney Disease

“…Propolis, a natural product rich in prenylated flavonoids, has been reported to exert versatile biological activities in our prior research, including anti-inflammasome [ 12 ], anti-oxidant [ 12 ], anti-diabetes [ 13 , 14 ] and anti-cancer properties [ 15 ]. Our recent rodent model of metabolic endotoxemia with obesity demonstrated that elimination of reactive oxygen species (ROS) using antioxidant therapy ameliorates kidney fibrosis as well as inflammation [ 16 ]. Considering pro-oxidant and pro-fibrotic effects of uremic retention solutes on human organ systems, the natural antioxidant PE may serve as a potential breakthrough treatment for AAs-induced nephropathy (AAN).…”