Protective Effect of Adalimumab on Diabetic Nephropathy by Regulating TNF-α Signal Pathway
Abstract
Background: To evaluate the inhibitory effect of adalimumab on diabetic nephropathyDN) through animal models.
Methods: We carried out the study in Weifang People’s Hospital, Weifang 261041, China in December 2020. Streptozotocin was used to induce DN in model animal Sprague-Dawley (SD) rats. The DN animal model was given treatment with adalimumab, and the inhibitory effect of adalimumab on the development process of DN was evaluated by detecting changes in blood glucose and urinary albumin levels. Meanwhile, the content of UN, Cr and CysC of the blood in different experimental groups was tested by weighing the ratio of kidney and performing ELISA to evaluate the protective effect of adalimumab on kidney of DN animal model. In addition, the changes in the transcription and translation levels of tumor necrosis factor α (TNF-α) and its downstream regulatory factors MCP-1 and NF-kB in kidney of different experimental groups were detected by fluorescence quantitative PCR and Western blot tests to further reveal the molecular mechanism of adalimumab inhibiting the diabetic nephropathy.
Results: adalimumab could significantly downregulate blood glucose and urinary albumin levels (P <0.05). The renal body weight ratio and the contents of UN, Cr and Cysc in blood in the adalimumab group were significantly lower than those in the placebo group (P <0.05). Meanwhile, adalimumab could significantly downregulate the expression of these molecules (P <0.05).
Conclusion: adalimumab could exert its therapeutic effect on diabetic nephropathy through its specific targeting TNF-α signaling pathways.
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14. Yi H, Peng R, Zhang LY, et al (2017). Lin-cRNA-Gm4419 knockdown ameliorates NF-κB/NLRP3 inflammasome-mediated inflammation in diabetic nephropathy. Cell Death Dis, 8(2): e2583.
15. Alicic RZ, Rooney MT, Tuttle KR (2017). Diabetic Kidney Disease: Challenges, Progress, and Possibilities. Clin J Am Soc Nephrol, 12(12): 2032-2045.
16. Voelker J, Berg PH, Sheetz M, et al (2017). Anti-TGF-β1 Antibody Therapy in Pa-tients with Diabetic Nephropathy. J Am Soc Nephrol, 28(3): 953-962.
17. Vallon V, Thomson SC (2020). The tubular hypothesis of nephron filtration and dia-betic kidney disease. Nat Rev Nephrol, 16(6): 317-336.
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19. Feigerlová E, Battaglia-Hsu SF (2017). IL-6 signaling in diabetic nephropathy: From pathophysiology to therapeutic perspec-tives. Cytokine Growth Factor Rev, 37: 57-65.
20. Papadopoulou-Marketou N, Kanaka-Gantenbein C, Marketos N, et al (2017). Biomarkers of diabetic nephropathy: A 2017 update. Crit Rev Clin Lab Sci, 54(5): 326-342.
21. Dai H, Liu Q, Liu B (2017). Research Pro-gress on Mechanism of Podocyte Deple-tion in Diabetic Nephropathy. J Diabetes Res, 2017: 2615286.
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24. Yang H, Xie T, Li D, et al (2019). Tim-3 ag-gravates podocyte injury in diabetic nephropathy by promoting macrophage activation via the NF-κB/TNF-α path-way. Mol Metab, 23: 24-36.
25. Croft M, Siegel RM (2017). Beyond TNF: TNF superfamily cytokines as targets for the treatment of rheumatic diseases. Nat Rev Rheumatol, 13(4): 217-233.
26. Panés J, Rimola J (2017). Perianal fistulizing Crohn's disease: pathogenesis, diagnosis and therapy. Nat Rev Gastroenterol Hepatol, 14(11): 652-664.
27. De la Cruz-Mosso U, García-Iglesias T, Bu-cala R, et al (2018). MIF promotes a dif-ferential Th1/Th2/Th17 inflammatory response in human primary cell cultures: Predominance of Th17 cytokine profile in PBMC from healthy subjects and in-crease of IL-6 and TNF-α in PBMC from active SLE patients. Cell Immunol, 324: 42-49.
28. Appiah MG, Park EJ, Darkwah S, Kawamo-to E, et al (2020). Intestinal Epithelium-Derived Luminally Released Extracellular Vesicles in Sepsis Exhibit the Ability to Suppress TNF-a and IL-17A Expression in Mucosal Inflammation. Int J Mol Sci, 21(22): 8445.
29. Abraham BP, Ahmed T, Ali T (2017). In-flammatory Bowel Disease: Pathophysi-ology and Current Therapeutic Ap-proaches. Handb Exp Pharmacol, 239: 115-146.
30. Cheng X, Shen Y, Li R (2014). Targeting TNF: a therapeutic strategy for Alzhei-mer's disease. Drug Discov Today, 19(11): 1822-1827.
31. Hasegawa E, Takeda A, Yawata N, et al (2019). The effectiveness of adalimumab treatment for non-infectious uveitis. Im-munol Med, 42(2): 79-83.
32. Taylor PC, Keystone EC, van der Heijde D, et al (2017). Baricitinib versus Placebo or adalimumab in Rheumatoid Arthritis. N Engl J Med, 376(7): 652-662.
33. Abbasi M, Mousavi MJ, Jamalzehi S, et al (2019). Strategies toward rheumatoid ar-thritis therapy; the old and the new. J Cell Physiol, 234(7): 10018-10031.
34. LaMattina KC, Goldstein DA (2017). ada-limumab for the treatment of uveitis. Ex-pert Rev Clin Immunol, 13(3):181-188.
35. Fleischmann R, Pangan AL, Song IH,et al (2019). Upadacitinib Versus Placebo or Adalimumab in Patients With Rheuma-toid Arthritis and an Inadequate Re-sponse to Methotrexate: Results of a Phase III, Double-Blind, Randomized Controlled Trial. Arthritis Rheumatol, 71(11): 1788-1800.
36. Frampton JE (2018). SB5: An adalimumab Biosimilar. BioDrugs, 32(5): 507-510.
37. Kaushik VV (2017). Review of Biosimilars of adalimumab. J Assoc Physicians India, 65 (5 Suppl): 15-21.
38. Zeng Z, Yuan Q, Yu R, Zhang J, Ma H, Chen S (2019). Ameliorative Effects of Probiotic Lactobacillus paracasei NL41 on Insulin Sensitivity, Oxidative Stress, and Beta-Cell Function in a Type 2 Dia-betes Mellitus Rat Model. Mol Nutr Food Res, 63(22): e1900457.
2. Shen Z, Fang Y, Xing T, et al (2017). Dia-betic Nephropathy: From Pathophysiol-ogy to Treatment. J Diabetes Res, 2017: 2379432.
3. A/L B Vasanth Rao VR, Tan SH, Can-dasamy M, et al (2019). Diabetic nephropathy: An update on pathogenesis and drug development. Diabetes Metab Syndr, 13(1): 754-762.
4. Malik S, Suchal K, Khan SI, et al (2017). Apigenin ameliorates streptozotocin-induced diabetic nephropathy in rats via MAPK-NF-κB-TNF-α and TGF-β1-MAPK-fibronectin pathways. Am J Physiol Renal Physiol, 313(2): F414-F422.
5. Xu X, Pan X, Li S (2020). Prospective analy-sis of the efficacy of beraprost sodium combined with alprostadil on diabetic nephropathy and influence on rennin-angiotensin system and TNF-α. Exp Ther Med, 19(1): 639-645.
6. Wu JJ, Valdecantos WC (2017). adalimumab in Chronic Plaque Psoriasis: A Clinical Guide. J Drugs Dermatol, 16(8): 779-790.
7. Elsakkar MG, Sharaki OA, Abdallah DM, et al (2016). adalimumab ameliorates OVA-induced airway inflammation in mice: Role of CD4(+) CD25(+) FOXP3(+) regulatory T-cells. Eur J Pharmacol, 786: 100-108.
8. Bellinvia S, Cummings JRF, Ardern-Jones MR, et al (2019). adalimumab Biosimilars in Europe: An Overview of the Clinical Evidence. BioDrugs, 33(3): 241-253.
9. Azushima K, Gurley SB, Coffman TM (2018). Modelling diabetic nephropathy in mice. Nat Rev Nephrol, 14(1): 48-56.
10. Mori KP, Yokoi H, Kasahara M, et al (2017). Increase of Total Nephron Albumin Fil-tration and Reabsorption in Diabetic Nephropathy. J Am Soc Nephrol, 28(1): 278-289.
11. Salem NA, El Helaly RM, Ali IM, et al (2020). Urinary Cyclophilin A and serum Cystatin C as biomarkers for diabetic nephropathy in children with type 1 dia-betes. Pediatr Diabetes, 21(5): 846-855.
12. Tesch GH (2017). Diabetic nephropathy - is this an immune disorder? Clin Sci (Lond), 131(16): 2183-2199.
13. Wada J, Makino H (2016). Innate immunity in diabetes and diabetic nephropathy. Nat Rev Nephrol, 12(1): 13-26.
14. Yi H, Peng R, Zhang LY, et al (2017). Lin-cRNA-Gm4419 knockdown ameliorates NF-κB/NLRP3 inflammasome-mediated inflammation in diabetic nephropathy. Cell Death Dis, 8(2): e2583.
15. Alicic RZ, Rooney MT, Tuttle KR (2017). Diabetic Kidney Disease: Challenges, Progress, and Possibilities. Clin J Am Soc Nephrol, 12(12): 2032-2045.
16. Voelker J, Berg PH, Sheetz M, et al (2017). Anti-TGF-β1 Antibody Therapy in Pa-tients with Diabetic Nephropathy. J Am Soc Nephrol, 28(3): 953-962.
17. Vallon V, Thomson SC (2020). The tubular hypothesis of nephron filtration and dia-betic kidney disease. Nat Rev Nephrol, 16(6): 317-336.
18. Zhang J, Liu J, Qin X (2018). Advances in early biomarkers of diabetic nephropathy. Rev Assoc Med Bras (1992), 64(1): 85-92.
19. Feigerlová E, Battaglia-Hsu SF (2017). IL-6 signaling in diabetic nephropathy: From pathophysiology to therapeutic perspec-tives. Cytokine Growth Factor Rev, 37: 57-65.
20. Papadopoulou-Marketou N, Kanaka-Gantenbein C, Marketos N, et al (2017). Biomarkers of diabetic nephropathy: A 2017 update. Crit Rev Clin Lab Sci, 54(5): 326-342.
21. Dai H, Liu Q, Liu B (2017). Research Pro-gress on Mechanism of Podocyte Deple-tion in Diabetic Nephropathy. J Diabetes Res, 2017: 2615286.
22. Pugliese G, Penno G, Natali A, et al (2020). Diabetic kidney disease: New clinical and therapeutic issues. Joint position state-ment of the Italian Diabetes Society and the Italian Society of Nephrology on "The natural history of diabetic kidney disease and treatment of hyperglycemia in patients with type 2 diabetes and im-paired renal function". J Nephrol, 33(1): 9-35.
23. Furuichi K, Shimizu M, Hara A, et al (2018). Diabetic Nephropathy: A Comparison of the Clinical and Pathological Features be-tween the CKD Risk Classification and the Classification of Diabetic Nephropa-thy 2014 in Japan. Intern Med, 57(23): 3345-3350.
24. Yang H, Xie T, Li D, et al (2019). Tim-3 ag-gravates podocyte injury in diabetic nephropathy by promoting macrophage activation via the NF-κB/TNF-α path-way. Mol Metab, 23: 24-36.
25. Croft M, Siegel RM (2017). Beyond TNF: TNF superfamily cytokines as targets for the treatment of rheumatic diseases. Nat Rev Rheumatol, 13(4): 217-233.
26. Panés J, Rimola J (2017). Perianal fistulizing Crohn's disease: pathogenesis, diagnosis and therapy. Nat Rev Gastroenterol Hepatol, 14(11): 652-664.
27. De la Cruz-Mosso U, García-Iglesias T, Bu-cala R, et al (2018). MIF promotes a dif-ferential Th1/Th2/Th17 inflammatory response in human primary cell cultures: Predominance of Th17 cytokine profile in PBMC from healthy subjects and in-crease of IL-6 and TNF-α in PBMC from active SLE patients. Cell Immunol, 324: 42-49.
28. Appiah MG, Park EJ, Darkwah S, Kawamo-to E, et al (2020). Intestinal Epithelium-Derived Luminally Released Extracellular Vesicles in Sepsis Exhibit the Ability to Suppress TNF-a and IL-17A Expression in Mucosal Inflammation. Int J Mol Sci, 21(22): 8445.
29. Abraham BP, Ahmed T, Ali T (2017). In-flammatory Bowel Disease: Pathophysi-ology and Current Therapeutic Ap-proaches. Handb Exp Pharmacol, 239: 115-146.
30. Cheng X, Shen Y, Li R (2014). Targeting TNF: a therapeutic strategy for Alzhei-mer's disease. Drug Discov Today, 19(11): 1822-1827.
31. Hasegawa E, Takeda A, Yawata N, et al (2019). The effectiveness of adalimumab treatment for non-infectious uveitis. Im-munol Med, 42(2): 79-83.
32. Taylor PC, Keystone EC, van der Heijde D, et al (2017). Baricitinib versus Placebo or adalimumab in Rheumatoid Arthritis. N Engl J Med, 376(7): 652-662.
33. Abbasi M, Mousavi MJ, Jamalzehi S, et al (2019). Strategies toward rheumatoid ar-thritis therapy; the old and the new. J Cell Physiol, 234(7): 10018-10031.
34. LaMattina KC, Goldstein DA (2017). ada-limumab for the treatment of uveitis. Ex-pert Rev Clin Immunol, 13(3):181-188.
35. Fleischmann R, Pangan AL, Song IH,et al (2019). Upadacitinib Versus Placebo or Adalimumab in Patients With Rheuma-toid Arthritis and an Inadequate Re-sponse to Methotrexate: Results of a Phase III, Double-Blind, Randomized Controlled Trial. Arthritis Rheumatol, 71(11): 1788-1800.
36. Frampton JE (2018). SB5: An adalimumab Biosimilar. BioDrugs, 32(5): 507-510.
37. Kaushik VV (2017). Review of Biosimilars of adalimumab. J Assoc Physicians India, 65 (5 Suppl): 15-21.
38. Zeng Z, Yuan Q, Yu R, Zhang J, Ma H, Chen S (2019). Ameliorative Effects of Probiotic Lactobacillus paracasei NL41 on Insulin Sensitivity, Oxidative Stress, and Beta-Cell Function in a Type 2 Dia-betes Mellitus Rat Model. Mol Nutr Food Res, 63(22): e1900457.
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| Issue | Vol 50 No 12 (2021) | |
| Section | Original Article(s) | |
| DOI | https://doi.org/10.18502/ijph.v50i12.7936 | |
| Keywords | ||
| Diabetic nephropathy Adalimumab Kidney TNF-α signal pathway | ||
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How to Cite
1.
Ding Z, Jiang H, Fan Y, Sun G. Protective Effect of Adalimumab on Diabetic Nephropathy by Regulating TNF-α Signal Pathway. Iran J Public Health. 2021;50(12):2536-2545.
