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  • Recent studies demonstrated FoxO a enhances

    2022-11-18

    Recent studies demonstrated FoxO3a enhances the protective functions of autophagy in response to environmental stress , . FoxO3a coordinately activates autophagy by binding directly to the promoters of autophagy-related genes, including LC3, Gabarapl1, Beclin1, and Atg12 in atrophied skeletal muscle CDK4 inhibitor , . Aberrantly low FoxO3a levels are important for the suppression of autophagy via transcriptional block of LC3 in idiopathic pulmonary fibrosis fibroblasts cultured on collagen . Thus, we hypothesized FoxO3a might also be relevant to inflammation-induced autophagy in odontoblasts.
    Introduction Lupus nephritis (LN) is a common and severe complications of systemic lupus erythematosus, with poor prognosis. It affects 30–60% of adult and 70% of pediatric lupus patients [1], [2], [3], [4], [5]. It may lead to permanent renal damage and chronic kidney disease [6], [7]. Renal involvement is also a principal cause of morbidity and mortality in lupus patients [1], [6]. Despite the great progresses in diagnosis, immunosuppressive therapies, and the supportive treatments, the complete remission rate of proliferative renal diseases in LN patients remains less than 50%. The incidence of end-stage renal disease (ESRD) due to LN remains no reduction (around 3.2–6.31 cases per million population [4], [8]). The standardized mortality ratios of LN patients range from 5.9 to 6.8 which is ∼6 times higher than that in general population [9], [10]. The poor disease outcome indicates that the mechanisms of LN disease and organ injuries are not thoroughly understood. Multiple processes and factors contribute to the LN pathogenesis (reviewed in [1], [11], [12]). Among them, immune complexes (ICs) are the key players in LN initiation and progression. Lupus nephritis has been regarded as a classic example of IC-mediated glomerulonephritis. Autoantibodies against double-stranded DNA [13], C1q [13], nucleosomes [14], collagens [15], aggrecan [15], and many other autoantigens, exhibit high prevalence and pathogenic potentials in LN [16]. In kidney, ICs mainly deposit in the mesangial, the subendothelial, or the subepithelial areas [17], and can contact with the glomerular endothelial cells (GECs) and affect their functions. GEC dysfunction is another key process in LN pathogenesis. GECs, together with podocytes and the glomerular basement membrane (GBM), made up the glomerular filtration barrier (GFB), which is the structural foundation of renal functions [18]. Investigating the effects of ICs on GECs, illustrating the mechanisms of GECs injuries and finding ways for GEC protections are important for understanding the pathogenesis of LN. Autophagy is a conserved catabolic process of lysosomal degradation of self-components, to recycle materials and energy resources, and to remove the damaged organelles, misfolded proteins, and invading pathogens, which is essential for cell homeostasis [19]. Autophagy plays protective roles and may serve as therapeutic targets in many diseases, including cardiovascular diseases [20], kidney diseases [21], neurodegenerative diseases [22], cancers [23], obesity and metabolic disorders [24]. Autophagy also helps to shape the immune system [25] and is involved in various autoimmune diseases, including LN [26]. Autophagy has multiple effects on endothelial functions, including nitric oxide production, angiogenesis, and thrombosis [27]. Singh et al reported that impaired endothelial autophagy altered cell architecture, leading to endothelial-to-mesenchymal transition. Mice with reduced endothelial autophagy exhibited increased susceptibility to organ fibrosis [28]. Fujii and colleagues demonstrated that self-aggregated antibodies could be internalized by endothelial cells via actin polymerization, which was important for autophagy process [29]. We have also previously reported the cytoprotective role of autophagy in podocytes [30]. In the present study, we investigated the effects of ICs on GECs autophagy, and may provide new views for the mechanisms of endothelial damage in LN.