Document Type : Original Article
Authors
1 Department of Nephrology, Wuhan Third Hospital, Tongren Hospital of Wuhan University, Wuhan 430060, China.
2 Department of Endocrine, Wuhan Third Hospital, Tongren Hospital of Wuhan University, Wuhan 430060, China.
Abstract
Background: Lupus nephritis (LN) refers to the injury caused by systemic lupus erythematosus (SLE) involving the kidneys. A previous study identified angiopoietin-like protein 4 (ANGPTL4) as a novel urinary biomarker for tracking disease activity in LN.
Objective: To investigate the detailed role and regulatory mechanism of ANGPTL4 in experimental models of LN.
Methods: MRL/lpr mice 11-week-old were injected with adeno-associated virus (AAV)-mediated ANGPTL4 short hairpin RNA (shRNA). At 16 and 20 weeks of age, 24-h urine samples were harvested to measure proteinuria levels. After the mice were sacrificed, blood and kidney tissues were harvested to examine serum creatinine (cr) and blood urea nitrogen (BUN) levels, kidney histological changes, and pro-inflammatory cytokine production. Additionally, the levels of NLRP3 inflammasome-associated molecules in mouse renal tissues were detected to clarify the underlying mechanism.
Results: The AAV-sh-ANGPTL4 injection significantly reduced the proteinuria, cr, and BUN levels in MRL/lpr mice. ANGPTL4 silencing ameliorated glomerular, tubular, and interstitial damage in mice, mitigating the pathological alternations of LN. In addition, ANGPTL4 knockdown repressed pro-inflammatory cytokine production in the kidneys. Mechanically, ANGPTL4 suppression inhibited NLRP3 inflammasome expression in renal tissues of mice.
Conclusion: ANGPTL4 silencing inhibits the NLRP3 inflammasome-mediated inflammatory response, thereby ameliorating LN in MRL/lpr mice.
Keywords
- Lv, F., et al., CD36 aggravates podocyte injury by activating NLRP3 inflammasome and inhibiting autophagy in lupus nephritis. 2022. 13(8): p. 729.
- Saxena, R., et al., Lupus nephritis: current update. 2011. 13(5): p. 240.
- Anders, H., et al., Lupus nephritis. 2020. 6(1): p. 7.
- Hu, C., et al., Lipidomics Revealed Aberrant Metabolism of Lipids Including FAHFAs in Renal Tissue in the Progression of Lupus Nephritis in a Murine Model. 2021. 11(3).
- Massicotte-Azarniouch, D., et al., Kidney thrombotic microangiopathy in lupus nephritis: Impact on treatment and prognosis. 2022. 31(10): p. 1175-1185.
- Mohamed, A., et al., Therapeutic advances in the treatment of SLE. 2019. 72: p. 218-223.
- Guo, M., et al., Alteration in gut microbiota is associated with dysregulation of cytokines and glucocorticoid therapy in systemic lupus erythematosus. 2020. 11(6): p. 1758-1773.
- Galaup, A., et al., Angiopoietin-like 4 prevents metastasis through inhibition of vascular permeability and tumor cell motility and invasiveness. 2006. 103(49): p. 18721-6.
- Zhu, P., et al., Angiopoietin-like 4: a decade of research. 2012. 32(3): p. 211-9.
- !!! INVALID CITATION !!! [11-13].
- Clement, L., et al., Podocyte-secreted angiopoietin-like-4 mediates proteinuria in glucocorticoid-sensitive nephrotic syndrome. 2011. 17(1): p. 117-22.
- Clement, L., et al., Circulating angiopoietin-like 4 links proteinuria with hypertriglyceridemia in nephrotic syndrome. 2014. 20(1): p. 37-46.
- Cara-Fuentes, G., et al., Angiopoietin-like-4 and minimal change disease. 2017. 12(4): p. e0176198.
- Al Shawaf, E., et al., ANGPTL4: A Predictive Marker for Diabetic Nephropathy. 2019. 2019: p. 4943191.
- Vanarsa, K., et al., Quantitative planar array screen of 1000 proteins uncovers novel urinary protein biomarkers of lupus nephritis. 2020. 79(10): p. 1349-1361.
- Patel, S.J.B., p. Biomedecine, and pharmacotherapie, Inflammasomes, the cardinal pathology mediators are activated by pathogens, allergens and mutagens: A critical review with focus on NLRP3. 2017. 92: p. 819-825.
- Yuan, F., et al., Involvement of the NLRC4-Inflammasome in Diabetic Nephropathy. 2016. 11(10): p. e0164135.
- Wu, H., et al., Organ-specific biomarkers in lupus. 2017. 16(4): p. 391-397.
- Wu, D., et al., Role of NLRP3 Inflammasome in Lupus Nephritis and Therapeutic Targeting by Phytochemicals. 2021. 12: p. 621300.
- Oliveira, C., et al., The Role of NLRP3 Inflammasome in Lupus Nephritis. 2021. 22(22).
- Lu, A., et al., Hyperactivation of the NLRP3 Inflammasome in Myeloid Cells Leads to Severe Organ Damage in Experimental Lupus. 2017. 198(3): p. 1119-1129.
- Fu, R., et al., Podocyte Activation of NLRP3 Inflammasomes Contributes to the Development of Proteinuria in Lupus Nephritis. 2017. 69(8): p. 1636-1646.
- Li, X., et al., 1,25-dihydroxyvitamin D3 ameliorates lupus nephritis through inhibiting the NF-κB and MAPK signalling pathways in MRL/lpr mice. 2022. 23(1): p. 243.
- Yang, C., et al., Immunological mechanisms and clinical implications of regulatory T cell deficiency in a systemic autoimmune disorder: roles of IL-2 versus IL-15. 2008. 38(6): p. 1664-76.
- Chen, K., et al., Complement factor B inhibitor LNP023 improves lupus nephritis in MRL/lpr mice. 2022. 153: p. 113433.
- Cabana-Puig, X., et al., Lactobacillus spp. act in synergy to attenuate splenomegaly and lymphadenopathy in lupus-prone MRL/ mice. 2022. 13: p. 923754.
- Li, S., et al., Reduced kidney lipoprotein lipase and renal tubule triglyceride accumulation in cisplatin-mediated acute kidney injury. 2012. 303(3): p. F437-48.
- Liu, G. and L.J.P. He, Epigallocatechin-3-Gallate Attenuates Adriamycin-Induced Focal Segmental Glomerulosclerosis via Suppression of Oxidant Stress and Apoptosis by Targeting Hypoxia-Inducible Factor-1α/ Angiopoietin-Like 4 Pathway. 2019. 103: p. 303-314.
- Baek, W., et al., Toll-like Receptor Signaling Inhibitory Peptide Improves Inflammation in Animal Model and Human Systemic Lupus Erythematosus. 2021. 22(23).
- Jiang, T., et al., Nrf2 suppresses lupus nephritis through inhibition of oxidative injury and the NF-κB-mediated inflammatory response. 2014. 85(2): p. 333-343.
- Guiteras, J., et al., Dual Costimulatory and Coinhibitory Targeting with a Hybrid Fusion Protein as an Immunomodulatory Therapy in Lupus Nephritis Mice Models. 2022. 23(15).
- Deshmane, S.L., et al., Monocyte chemoattractant protein-1 (MCP-1): an overview. J Interferon Cytokine Res, 2009. 29(6): p. 313-26.
- Kulkarni, O. and H.J. Anders, Chemokines in lupus nephritis. Front Biosci, 2008. 13: p. 3312-20.
- Jia, C., et al., κSilencing of Angiopoietin-Like Protein 4 (Angptl4) Decreases Inflammation, Extracellular Matrix Degradation, and Apoptosis in Osteoarthritis via the Sirtuin 1/NF-B Pathway. 2022. 2022: p. 1135827.
- Zuo, Y., et al., viaANGPTL4 Regulates Psoriasis Modulating Hyperproliferation and Inflammation of Keratinocytes. 2022. 13: p. 850967.
- Guo, L., et al., Silencing Angiopoietin-Like Protein 4 (ANGPTL4) Protects Against Lipopolysaccharide-Induced Acute Lung Injury Via Regulating SIRT1 /NF-kB Pathway. 2015. 230(10): p. 2390-402.
- Kahlenberg, J. and M.J.C.o.i.r. Kaplan, The inflammasome and lupus: another innate immune mechanism contributing to disease pathogenesis? 2014. 26(5): p. 475-81.
- Zhao, J., et al., Curcumin attenuates murine lupus via inhibiting NLRP3 inflammasome. 2019. 69: p. 213-216.
- Peng, X., et al., Piperine ameliorated lupus nephritis by targeting AMPK-mediated activation of NLRP3 inflammasome. 2018. 65: p. 448-457.
- Su, B., et al., Icariin alleviates murine lupus nephritis via inhibiting NF-κB activation pathway and NLRP3 inflammasome. 2018. 208: p. 26-32.