Evaluation of the level of prostaglandin E2, thromboxane B2 and leukotriene B4 in kidneys in simulated Hayman's nephritis under the influence of cell-free cryopreserved biological agents
Keywords:
cell-free cryopreserved biological agents, autoimmune diseases, spleen cryoextract, placenta cryoextract, mesenchymal stem cell conditioned medium, membranous nephropathyAbstract
Introduction. A kidney disease characterized by the deposition of immune complexes on the glomerular basement membrane is called membranous nephropathy (MN). Although the ultimate goal of treatment for this organ-specific autoimmune disease is to terminate the immune response to PLA2R or other podocyte antigens, the slow decline in circulating antibody titers after treatment puts podocytes at risk of further damage. Cell-free cryopreserved biological agents (CFCBA), in particular, cryopreserved placental extract (CEP), spleen cryoextract (CES) and conditioned medium of mesenchymal stem cells (MSC-CM) attracted our attention as potential means for the treatment of patients with MN. The purpose of the study is to characterize the level of prostaglandin (Pg) E2, thromboxane (Tx) B2 and leukotriene (LT) B4 in the kidneys of rats with simulated Heyman's nephritis under the influence of cell-free cryopreserved biological agents. Materials and methods. Autoimmune nephritis (AIN) was reproduced according to the method of Heymann W.R. and sang Research on the effectiveness of CFCBA in AIN was conducted on 42 male sheep. On the 70-th day of the experiment, the rats were removed from the experiment and the kidneys were excised. To obtain a homogenate, the kidneys were washed with cold (+4°C) isotonic 1.15% KCl solution and homogenized. The content of PgE2, LTB4 and TxB2 was determined by the enzyme-linked immunosorbent assay method using standard kits for enzymelinked immunosorbent assay (Neogen Corporation, USA). Research results and their discussion. Experimental studies have shown that in rats, against the background of the development of AIN, there is a multiple increase in the content of eicosanoids in the kidney tissue. The use of the reference drug canefron caused a decrease in the content of the studied eicosanoids in the kidney tissues of rats with AIN by 19.0–23.6% on average. Against the background of the introduction of the investigated CFCBA, the most pronounced changes were noted from the side of LTB4 content. The evaluation of the level of TxB2 in the kidneys of rats with AIN against the background of CFCBA administration showed that the specified eicosanoid decreased most significantly (р˂0.001) against the background of MSC-CM application (44.4%). The introduction of CES and CEP led to a relative decrease in the level of PgE2 in the kidney tissues of rats with AIN by 26.4% (p˂0.001) and 26.7% (p˂0.001), respectively. Conclusions. Against the background of the introduction of CEP, the content of LTB4 in rats with AIN decreased (p=0.005) by 42.9%. The assessment of the PgE2 content in the kidney tissues of rats with AIN showed that the most clearly indicated indicator decreased (р˂0.001) against the background of the introduction of MSC-CM (43.5%). Similarly, the content of TxB2 decreased most significantly (р˂0.001) against the background of the use of MSC-CM (44.4%).
References
Jefferson JA, Nelson PJ, Najafian B, Shankland SJ. Podocyte disorders: core curriculum 2011. American Journal of Kidney Diseases. 2011;58(4):666–677. DOI: https://doi.org/10.1053/j.ajkd.2011.05.032
Kwiatkowska E, Stefańska K, Zieliński M, Sakowska J, Jankowiak M, Trzonkowski P, Marek-Trzonkowska N, Kwiatkowski S. Podocytes – the most vulnerable renal cells in preeclampsia. International Journal of Molecular Sciences. 2020;21(14):5051. DOI: https://doi.org/10.3390/ijms21145051
Issa W, Njeim R, Carrazco A, Burke GW, Mitrofanova A. Role of the innate immune response in glomerular disease pathogenesis: focus on podocytes. Cells. 2024;13(13):1157. DOI: https://doi.org/10.3390/cells13131157
Sinico RA, Mezzina N, Trezzi B, Ghiggeri GM, Radice A. Immunology of membranous nephropathy: from animal models to humans. Clinical and Experimental Immunology. 2016;183(2):157–165. DOI: https://doi.org/10.1111/cei.12729
McGrogan A, Franssen CF, de Vries CS. The incidence of primary glomerulonephritis worldwide: a systematic review of the literature. Nephrology Dialysis Transplantation. 2011;26(2):414–430. DOI: https://doi.org/10.1093/ndt/gfq665
Dantas M, Silva LBB, Pontes BTM, Dos Reis MA, de Lima PSN, Moysés Neto M. Membranous nephropathy. Brazilian Journal of Nephrology. 2023;45(2):229–243. DOI: https://doi.org/10.1590/2175-8239-JBN-2023-0046en
Ma H, Sandor DG, Beck LH Jr. The role of complement in membranous nephropathy. Seminars in Nephrology. 2013;33(6):531–542. DOI: https://doi.org/10.1016/j.semnephrol.2013.08.004
Kistler AD, Salant DJ. Complement activation and effector pathways in membranous nephropathy. Kidney International. 2024;105(3):473–483. DOI: https://doi.org/10.1016/j.kint.2023.10.035
Fujigaki Y, Nagase M, Honda N. Intraglomerular basement membrane translocation of immune complex (IC) in the development of passive in situ IC nephritis of rats. The American Journal of Pathology. 1993;142(3):831–842.
Beck LH Jr, Salant DJ. Membranous nephropathy: from models to man. Journal of Clinical Investigation. 2014;124(6):2307–2314. DOI: https://doi.org/10.1172/JCI72270
Beck LH Jr, Fervenza FC, Beck DM, Bonegio RG, Malik FA, Erickson SB, Cosio FG, Cattran DC, Salant DJ. Rituximabinduced depletion of anti-PLA2R autoantibodies predicts response in membranous nephropathy. Journal of the American Society of Nephrology. 2011;22(8):1543–1550. DOI: https://doi.org/10.1681/ASN.2010111125
Takano T, Elimam H, Cybulsky AV. Complement-mediated cellular injury. Seminars in Nephrology. 2013;33(6):586–601. DOI: https://doi.org/10.1016/j.semnephrol.2013.08.009
Hladkykh FV. Evaluation of tentative and research activity in rats with experimental allergic encephalomyelitis against the administration of cell-free cryopreserved biological agents. Psychiatry, Neurology and Medical Psychology. 2024;11(2(24)):124–137. DOI: https://doi.org/10.26565/2312-5675-2024-24-02
Hladkykh FV. Nonsteroidal anti-inflammatory drugs: therapeutic and undesirable effects, ways of their optimization. Vinnytsia, 2022. 216 p. DOI: https://doi.org/10.46879/2022.1
Koshurba IV, Hladkнkh FV, Chyzh MO. Assessment of antiulcerogenic effect of cryopreserved placenta extract on the model of alcohol-prednisolone damage of the stomach. Medical science of Ukraine. 2022;18(2):3–9. DOI: https://doi.org/10.32345/2664-4738.2.2022.01
Hladkykh FV. Prospects for the use of immunomodulators in the treatment of patients with autoimmune diseases: focus on extracts of biological tissues (cryoextract of the placenta and cryoextract of the spleen). Immunology and allergology: science and practice. 2023;4:29–46. DOI: https://doi.org/10.37321/immunology.2023.4-04
Heymann W, Kmetec EP, Wilson SG, Hunter JL, Hackel DB, Okuda R, Cuppage F. Experimental autoimmune renal disease in rats. Annals of the New York Academy of Sciences. 1965;124(1):310–322. DOI: https://doi.org/10.1111/j.1749-6632.1965.tb18966.x
Freund J. Some aspects of active immunization. Annual Review of Microbiology. 1947;1:291–308. DOI: https://doi.org/10.1146/annurev.mi.01.100147.001451
Shebeko SK. Experimental substantiation of the combined use of amino sugar derivatives and flavonoids in the therapy of chronic kidney disease. Dissertation. Kharkiv, 2017. 516 p. Access: https://nrat.ukrintei.ua/searchdoc/0521U100125/
Deepthi R, Suhasin G. A review on animal models of chronic kidney disease – an update. Biomedical and Pharmacology Journal. 2023;16(3):1319–1327. DOI: https://dx.doi.org/10.13005/bpj/2711
Zahraa Mohammed-Ali, Rachel E. Carlisle, Samera Nademi, Jeffrey G. Dickhout, Chapter 16 – Animal Models of Kidney Disease. 2017:379–417. DOI: https://doi.org/10.1016/B978-0-12-809468-6.00016-4
Jefferson JA, Pippin JW, Shankland SJ. Experimental models of membranous nephropathy. Drug Discovery Today: Disease Models. 2010;7(1–2):27–33. DOI: https://doi.org/10.1016/j.ddmod.2010.11.001
Becker GJ, Hewitson TD. Animal models of chronic kidney disease: useful but not perfect. Nephrology Dialysis Transplantation. 2013;28(10):2432–2438. DOI: https://doi.org/10.1093/ndt/gft071
Wang YM, Lee VWS, Wu H, Harris DCH, Alexander SI. Heymann nephritis in Lewis rats. Current Protocols in Immunology. 2015;109:15.29.1–15.29.6. DOI: https://doi.org/10.1002/0471142735.im1529s109
Shtryhol SYu, Lisovyi VM, Zupanets IA, Shebeko SK, Maslova NF, Hozhenko AI, Kharchenko DS. Methods of experimental modeling of kidney damage for pharmacological research: methodical recommendations. Kharkiv, 2009. 48 p.
Podpletnia OA, Khomyak NV, Sokolova KV, Kaidash SP, Khomyak OV. Phytotherapeutic drugs with nephroprotective activity (review). Medical perspectives. 2017;22(17):10–17. DOI: https://doi.org/10.26641/2307-0404.2017.1.100866
Shebeko SK, Chernykh VV, Zupanets KO. Nephroprotective effect of the herbal composition BNO 2103 in rats with renal failure. Health of Man. 2021;4:48–56. DOI: https://doi.org/10.30841/2307-5090.4.2021.252396
Monatko KV. Experimental study of the nephroprotective effect of freeze-dried watermelon powder. Dissertation. Kharkiv, 2014. 217 p. Access: https://nrat.ukrintei.ua/searchdoc/0414U004729/
Borisov SO, Kolosov OM, Kostev FI, Borisov OV. Study of the functional state of the kidneys of rats with acute pyelonephritis on the background of diabetes under the conditions of drug exposure in the experiment. Health of Man. 2020;72(1):80–83. DOI: https://doi.org/10.30841/2307-5090.1.2020.205494
Rybolovlev YuR, Rybolovlev RS. Dosage of substances for mammals according to biological activity constants. Proceedings of the Academy of Sciences of the USSR. 1979;247(6):1513–1516.
Shepitko VI. Structural and functional indicators of the cryopreserved liver and the effect of its transplantation on the morphofunctional state of a number of internal organs: dissertation. Dissertation. Kharkiv, 2004. 326 p. Access: https://nrat.ukrintei.ua/searchdoc/0504U000610/
Bespalova IG. Peptide composition and biological action of extracts of cryopreserved pig spleen fragments and piglet skin. Dissertation. Kharkiv, 2016. 162 p. Access: https://nrat.ukrintei.ua/searchdoc/0416U004539/
Golubinskaya PA, Sarycheva MV, Dolzhikov AA, Bondarev VP, Stefanova MS, Soldatov VO, Nadezhdin SV, Korokin MV, et al. Application of multipotent mesenchymal stem cell secretome in the treatment of adjuvant arthritis and contact-allergic dermatitis in animal models. Pharmacy & Pharmacology. 2020;8(6):416–425. DOI: https://doi.org/10.19163/2307-9266-2020-8-6-416-425
Globa VYu. Use of cryopreserved cell cultures and neurotrophic factors in experimental infravesical obstruction. Dissertation. Kharkiv, 2021. 156 p. Access: https://nrat.ukrintei.ua/searchdoc/0821U100913/
Zar J.H. Biostatistical analysis (5 ed.). Prentice-Hall, Englewood. 2014; 960 р.
Cybulsky AV, Papillon J, McTavish AJ. Complement activates phospholipases and protein kinases in glomerular epithelial cells. Kidney International. 1998;54(2):360–372. DOI: https://doi.org/10.1046/j.1523-1755.1998.00013.x
Cybulsky AV, Takano T, Papillon J, McTavish AJ. Complement-induced phospholipase A2 activation in experimental membranous nephropathy. Kidney International. 2000;57(3):1052-62. DOI: https://doi.org/10.1046/j.1523-1755.2000.00932.x
Takano T, Cybulsky AV. Complement C5b-9-mediated arachidonic acid metabolism in glomerular epithelial cells: role of cyclooxygenase-1 and -2. The American Journal of Pathology. 2000;156(6):2091–2101. DOI: https://doi.org/10.1016/S0002-9440(10)65080-8
Li Y, Yan M, Yang J, Raman I, Du Y, Min S, Fang X, Mohan C, Li QZ. Glutathione S-transferase Mu 2-transduced mesenchymal stem cells ameliorated anti-glomerular basement membrane antibody-induced glomerulonephritis by inhibiting oxidation and inflammation. Stem Cell Research & Therapy. 2014;5(1):19. DOI: https://doi.org/10.1186/scrt408
