**1. Introduction**

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease with complex pathogenesis, characterized by formation of autoantibodies against normal structures of the body such as skin, joints, blood elements, kidney, and central nervous system, with a heterogeneity of clinical manifestations. Skin lesions are frequent, such as symmetric malar erythema, photo sensibility, hyperkeratosis, ecchymosis, oral or mucosal ulcerations, alopecia. Proteinuria or nephrotic syndrome, changes in urinary sediment, increase in serum creatinine and arterial hypertension are clinical manifestations of lupus nephritis [1,2]. SLE—Autoimmune prototype disease—is characterized by abnormal responses of T and B immune cells with excessive synthesis of autoantibodies and immune circulant complexes [3] associated with nonimmune factors [4,5].

SLE clinical evolution is variable, being influenced by genetic factors, external factors, and human body resources. The pathogenic mechanism is promoted by the UV

**Citation:** Ene, C.D.; Georgescu, S.R.; Tampa, M.; Matei, C.; Mitran, C.I.; Mitran, M.I.; Penescu, M.N.; Nicolae, I. Cellular Response against Oxidative Stress, a Novel Insight into Lupus Nephritis Pathogenesis. *J. Pers. Med.* **2021**, *11*, 693. https://doi.org/ 10.3390/jpm11080693

Academic Editor: Jun Fang

Received: 22 June 2021 Accepted: 19 July 2021 Published: 22 July 2021

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exposure of keratinocytes. Keratinocyte activation induces chemokines synthesis (CXCL5, CXCL8, CXCL20), production of adhesion molecules, apoptosis, keratinocyte photodistruction, release of nuclear and cytoplasmic antigens, and immune response initiation. These pathogenic events are processed by dermic and epidermic macrophages and presented to dermal naïve T lymphocytes. In SLE-related skin lesions, vacuolar and hydropic degeneration of keratinocytes and lymphocytic infiltration in papillary dermis could be found. Direct immunofluorescence reveals deposition in band of antibodies and complement to the dermo–epidermic junction. The cascade of autoantibodies induces the formation of circulant immune complexes, with preferential deposition in the synovial joint and glomeruli. The forms of LE limited to skin can evolve to SLE [6,7].

Oxidative stress in SLE was intensively studied during years. Reactive oxygen species (ROS) interaction with lipids, proteins, nucleic acids and hydro carbonates promotes acute and chronic tissue damage, mediates immunomodulation and trigger autoimmunity in SLE subjects [8–11]. Moreover, for their viability and correct functions, the cells develop endogenous strategies for suppression or modulating oxidative stress [3,12–14]. High levels of oxidative and nitrosative stress markers were determined in SLE patients with high disease activity. Still, oxidative stress influence immune and nonimmune cells on determining the disease phenotype in each subject [12]. An imbalance in oxidant/antioxidant equilibrium in autoimmune disease by endogenous or exogenous toxic factors exposure, by alteration of tissue damage response/repair mechanisms induces an aberrant activity of innate and adaptative immune response, high production of autoantibodies, multiple lesions of tissues and organs [4]. The bidirectional relation between oxidative stress and immune response, considered as part of autoimmune physiopathology, could change the paradigm of a disease characterized by perturbation of immune system and high production of autoantibodies [5,15–17].

A large diversity of lipoperoxides were detected in SLE in extracellular fluids and in blood. They influence disease expression by their effect on immune and non-immune cells [16,18]. Lipid peroxidation generates a variety of metabolites, the best known being saturated monoaldehydes; unsaturated aldehydes; dicarbonyls; malondialdehyde; 4-oxo-2-nonenal; hydroxydialdehydes (4-hydroxy-2-nonenal, 4-hydroxy-2-hexenal); oxidized phospholipids [8,19–21]. High levels of oxidative and nitrosative stress were detected in patients with active SLE, suggesting a link between lipoperoxidation and disease activity. Increased activity of malondialdehyde (MDA), 4-hydroxy-2-nonenal (HNE), MDA-protein adduct, HNE-protein adduct, superoxide dismutase (SOD), nitric oxide synthase (INOS), anti-MDA and anti-HNE antibodies were correlated in SLE patients with SLEDAI over 6 [9,16,21]. These lipoperoxides' destructive effect could be limited by defense mechanisms of the human organism, such as lipoperoxides metabolization by oxide reductase (aldoceto-reductase, aldehyde-dehydrogenase, alcohol-dehydrogenase, glutathione-S-transferase) and cellular antioxidant defense mechanisms that include enzymes (SOD, chloramphenicol acetyltransferase—CAT, glutathione peroxidase—GPx, reductase—GR, Stransferases—GST, tioredoxin-reductase, hemoxigenase), non-enzymes (A, C, E vitamins), and carotenoids, flavonoids, glutathione and other antioxidant minerals [13,18]. Defense mechanism disruption was associated with clinical complications of SLE [10,11,16]. Isoprostan F2 (8-iso-PGF2) levels, a results of lipid peroxidation, was correlated with disease activity in SLE subjects. Moreover, high levels of MDA, F2-Isoprostan, nitric oxide and low levels of reduced glutathione were determined in patients with lupus nephritis [16].

In SLE, oxidative stress is involved in the formation of advanced glycation end products (AGEs) and advanced lipoperoxidation end products (ALEs), compounds with proinflammatory characteristics. AGEs and ALEs synthesis is realized through condensation reactions between electrophile and nucleophile reactants [17,21–25]. AGEs and ALEs are immunogen and they determine antibodies synthesis. AGEs initiate signaling cascades by specific receptors named RAGE. No data could be found in the literature about a receptormediated mechanism regarding the destructive effect of ALEs [21]. RAGE polymorphisms

were associated with SLE susceptibility and lupus nephritis [26]. sRAGE could exert benefic effects by preventing proinflammatory signaling, they act as bait receiver [25,27–31].

In systemic autoimmune diseases, ROS and RNS overproduction induce DNA integrity alteration, damage of DNA response and repair (DDR/R) mechanisms, accumulation of mono- and double catenary cytosolic DNA, activation of stimulator of interferon genes (STING), synthesis of type 1 interferon [32]. DDR/R recognize defects during cell cycle and assures their correct reparation. In case of unrepaired lesions, the cell transmits the mutant genome to its descendants, otherwise it is neutralized by apoptosis or senescence [3,32,33].

The most frequent oxidative lesion in aerobe organisms is the formation of 7,8-dihydro-8-oxo-2′ -deoxyguanosin (8-oxo-dG or 8-OH dG) [17,34,35]. In normal cells, during DNA replication, 2-deoxyguaninae (dG) is associated with 2′ -deoxycitosine (dC). In tissues with high levels of oxidative stress, dG could wrongly link 2′ -deoxyadenine (dA) and could induce G → C at T → A transversion. If 8-OHdG is not efficiently eliminated, it accumulates in tissue and induces genomic instability and cells dysfunctions [17,32,33,35]. Usually, 8 oxoguanine-DNA-glycosylase (OGG1) is responsible for 8-OH-dG clean-up. OGG1 deficit induces high levels of 8-OH-dG in DNA. OGG1 overexpression in mitochondria improves its function, cell survival and reduces the number of DNA lesions by 8-OH-dG reparation in oxidative stress conditions, in vitro. These data suggest that OGG1 could play a protective role in inflammatory diseases. OGG1 polymorphism could offer susceptibility to lupus nephritis and modulate 8-OH-d G serum level in SLE patients [36–38].

Carbonylated proteins, nitrotyrosine and oxidated glutathione are stable chemical products and they are used as biomarkers in SLE [16]. Increased levels of nitrates, nitrites, homocysteine and oxidated serum proteins are associated with tissue lesions and SLE activity. High SLEDAI was correlated with low serum albumin in lupus nephritis [15]. Some studies in the last few years showed that thiol-disulfides interconversion plays a crucial role in antioxidant defense, apoptosis, detoxification, transcription, enzymatic activity regulation [20,37,38].

All these data suggest that SLE patients have high risk of developing oxidative stressassociated inflammatory response. The effects of pharmacological therapies on oxidative stress depend on chemical characteristics of reactive metabolites and action mechanisms consequences. Based on these data, the present study tries to determine a pattern of oxidative stress markers and endogenous strategies for suppression/modulating oxidative stress in SLE patients. The aim of the study was to detect deficiencies in protective system of cells in order to minimize the consequences of oxidative stress and to identify individualized pharmacological targets in SLE patients.
