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      Ceftriaxone Calcium Crystals Induce Acute Kidney Injury by NLRP3-Mediated Inflammation and Oxidative Stress Injury


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          To investigate the role of inflammatory reactions and oxidative stress injury in the mechanisms of ceftriaxone calcium crystal-induced acute kidney injury (AKI) both in vivo and in vitro.


          Male Sprague Dawley rats were randomly divided into five groups of ten each according to different concentrations of ceftriaxone and calcium. Based on the levels of serum creatinine (Scr) and blood urea nitrogen (BUN), the AKI group was chosen for the subsequent experiments. Kidney histological examination and immunohistochemistry were performed. The expression of NLRP3 and IL-1 β protein and the concentrations of oxidative stress markers such as ROS, MDA, and H 2O 2 in kidney tissues were estimated. In parallel, HK-2 human renal proximal tubule cells were exposed to ceftriaxone calcium crystals. The mRNA expression levels of NLRP3 and IL-1 β and the concentrations of oxidative stress markers were evaluated. Finally, cell viability and rat survival were also assessed.


          The results showed that significantly increased Scr and BUN levels, consistent with morphological changes and kidney stones, were found in the rats that received the highest concentration of ceftriaxone (1000 mg/kg) combined with calcium (800 mg/kg). The activation of the NLRP3 inflammasome axis and the marked elevation of MDA, H 2O 2, and ROS levels were observed both in vivo and in vitro. High expression of Nrf2, HO-1, and NQO1 was also documented. In addition, cell apoptosis and rat mortality were promoted by ceftriaxone calcium crystals.


          Notably, we found that ceftriaxone-induced urolithiasis was associated with a high risk of AKI and NLRP3-mediated inflammasome and oxidative stress injury were of major importance in the pathogenesis.

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          Most cited references 29

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          The immune system and kidney disease: basic concepts and clinical implications.

          The kidneys are frequently targeted by pathogenic immune responses against renal autoantigens or by local manifestations of systemic autoimmunity. Recent studies in rodent models and humans have uncovered several underlying mechanisms that can be used to explain the previously enigmatic immunopathology of many kidney diseases. These mechanisms include kidney-specific damage-associated molecular patterns that cause sterile inflammation, the crosstalk between renal dendritic cells and T cells, the development of kidney-targeting autoantibodies and molecular mimicry with microbial pathogens. Conversely, kidney failure affects general immunity, causing intestinal barrier dysfunction, systemic inflammation and immunodeficiency that contribute to the morbidity and mortality of patients with kidney disease. In this Review, we summarize the recent findings regarding the interactions between the kidneys and the immune system.
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            Soluble Uric Acid Activates the NLRP3 Inflammasome

            Uric acid is a damage-associated molecular pattern (DAMP), released from ischemic tissues and dying cells which, when crystalized, is able to activate the NLRP3 inflammasome. Soluble uric acid (sUA) is found in high concentrations in the serum of great apes, and even higher in some diseases, before the appearance of crystals. In the present study, we sought to investigate whether uric acid, in the soluble form, could also activate the NLRP3 inflammasome and induce the production of IL-1β. We monitored ROS, mitochondrial area and respiratory parameters from macrophages following sUA stimulus. We observed that sUA is released in a hypoxic environment and is able to induce IL-1β release. This process is followed by production of mitochondrial ROS, ASC speck formation and caspase-1 activation. Nlrp3 −/− macrophages presented a protected redox state, increased maximum and reserve oxygen consumption ratio (OCR) and higher VDAC protein levels when compared to WT and Myd88 −/− cells. Using a disease model characterized by increased sUA levels, we observed a correlation between sUA, inflammasome activation and fibrosis. These findings suggest sUA activates the NLRP3 inflammasome. We propose that future therapeutic strategies for renal fibrosis should include strategies that block sUA or inhibit its recognition by phagocytes.
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              Pattern recognition receptors and the inflammasome in kidney disease.

              Toll-like receptors (TLRs) and nucleotide-binding oligomerization domain receptors (NLRs) are families of pattern recognition receptors that, together with inflammasomes, sense and respond to highly conserved pathogen motifs and endogenous molecules released upon cell damage or stress. Evidence suggests that TLRs, NLRs and the NACHT, LRR and PYD domains-containing protein 3 (NLRP3) inflammasome have important roles in kidney diseases through regulation of inflammatory and tissue-repair responses to infection and injury. In this Review, we discuss the pathological mechanisms that are related to TLRs, NLRs and NLRP3 in various kidney diseases. In general, these receptors are protective in the host defence against urinary tract infection, but can sustain and self-perpetuate tissue damage in sterile inflammatory and immune-mediated kidney diseases. TLRs, NLRs and NLRP3, therefore, have become promising drug targets to enable specific modulation of kidney inflammation and suppression of immunopathology in kidney disease.

                Author and article information

                Oxid Med Cell Longev
                Oxid Med Cell Longev
                Oxidative Medicine and Cellular Longevity
                9 July 2020
                : 2020
                1Department of Urology, Nanjing First Hospital, Nanjing Medical University, 68 Changle Road, Nanjing 210006, China
                2Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, No. 321, Zhongshan Road, Nanjing 210000, China
                Author notes

                Academic Editor: Maria U. Moreno

                Copyright © 2020 Zhang Yifan et al.

                This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                Funded by: National Natural Science Foundation of China
                Award ID: 81570613
                Award ID: 81370853
                Funded by: Jiangsu Provincial Social Development Project
                Award ID: BE2017615
                Funded by: Jiangsu Provincial Medical Innovation Team
                Research Article

                Molecular medicine


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