The combination of vitamin D3 and erythropoietin alleviates acute kidney injury induced by ischemia-reperfusion via inhibiting inflammation and apoptosis

Document Type : Original Article

Authors

1 Department of Nephrology, Guizhou Provincial People’s Hospital & NHC Key Laboratory of Pulmonary Immunological Disease (Guizhou Provincial People’s Hospital), Guiyang, Guizhou, 550002, P.R. China

2 Department of Operating Room, The First Affiliated Hospital of Guizhou University of traditional Chinese medicine, Guiyang, Guizhou, 550001, P.R. China

Abstract

Objective(s): Acute renal ischemia may cause acute renal dysfunction due to lack of blood supply; the manifestations are renal tubular cell apoptosis, infiltration of macrophages, and microvascular destruction. Many studies have shown that erythropoietin (EPO) and vitamin D3 (VD3) can be used to prevent or treat renal ischemia-reperfusion (I/R) injury, and VD3 may interact with EPO. In the present study, the effects of the combination of VD3 and EPO in I/R acute kidney injury were studied.
Materials and Methods: Rats were divided into 5 groups: sham-operated (SHAM), AKI without treatment (AKI-control), AKI treatment with VD3(AKI+VD3), AKI treatment with EPO(AKI+EPO), AKI treatment with VD3 and EPO(AKI+VD3+EPO). The effects of the combination of VD3 and EPO on AKI were assessed by histologic, inflammation, and apoptosis studies.
Results: The degree of damage in renal tissue was significantly reduced in VD3, EPO, and combined groups. Combination therapy with VD3 and EPO markedly improved Creatinine clearance rate (CCr). The combined treatment group showed the lowest F4/80+ and CD68+ expressions. The expression of Bcl-2 in the combined treatment group was higher than those in VD3 group and the EPO group, while Bax’s expression goes in the opposite direction.
Conclusion: This provides further evidence that VD3 and EPO have beneficial effects in I/R injury via anti-inflammatory and anti-apoptosis pathways. The synergistic protective effect of VD3 and EPO is of profound significance in the development of new strategies for the prevention and treatment of acute kidney injury (AKI).

Keywords

References

1. Nattachai S, Win K, Noppathorn M, Cameron H, Kearkiat P, Nuttha L, et al. The epidemiology and characteristics of acute kidney injury in the southeast asia intensive care unit: a prospective multicentre study. Nephrol Dial Transplant 2020; 10:1729-1738.
2. Yang Li. Acute kidney injury in asia. Kidney Dis 2016; 2:95-102.
3. Wan L, Bagshaw SM, Langenberg C, Saotome T, Bellomo R. Pathophysiology of septic acute kidney injury: what do we really know?. Crit care Med 2008; 36:198-203.
4. Savige J, Gregory M, Gross O, Kashtan C, Ding J, Flinter F. Expert guidelines for the management of alport syndrome and thin basement membrane nephropathy. J Am Soc Nephrol 2013; 24:364-375.
5. Andrew JP. Lewington, Jorge Cerdá, Ravindra L. Mehta. Raising awareness of acute kidney injury: a global perspective of a silent killer. Kidney Int 2013; 84:457-467.
6. Wang Y, Fang Y, Teng J, Ding X. Acute Kidney Injury Epidemiology: From Recognition to Intervention. Contrib Nephrol 2016;187:1-8.
7. Evangelia S, Ioannis T, George K, Evangelia D, Constantina S, Olympia GT, et al. Erythropoietin attenuates renal injury in experimental acute renal failure ischaemic/reperfusion model. Nephrol Dial Transplant 2006; 21:330-336.
8. Levinsky, Norman G. Pathophysiology of acute renal failure.  N Engl J Med 1977; 296:1453-1458.
9. Dos Anjos Cassado A. F4/80 as a major macrophage marker: the case of the peritoneum and spleen. Results Probl Cell Differ 2017; 62:161-179.
10. Chistiakov DA, Killingsworth MC, Myasoedova VA, Orekhov AN, Bobryshev YV. CD68/macrosialin: not just a histochemical marker. Lab Invest 2017; 97:4-13.
11. Korsmeyer SJ, Shutter JR, Veis DJ, Merry DE, Oltvai ZN, et al. Bcl-2/bax: a rheostat that regulates an anti-oxidant pathway and cell death. Semin Cancer Biol 1993; 4:327-332.
12. Kuwana T, Newmeyer DD. Bcl-2 family proteins and the role of mitochondria in apoptosis. Curr Opin Cell Biol 2003; 15:691-699.
13. Kwon MS, Kim MH, Kim SH, Park KD, Yoo SH, Oh IU, et al. Erythropoietin exerts cell protective effect by activating PI3K/Akt and MAPK pathways in C6 Cells. Neurol Res 2014; 36:215-223.
14. Li XJ, Zhang GX, Sun N, Sun Y, Yang LZ, Du YJ, et al. Protective effects of erythropoietin on endotoxin-related organ injury in rats. J Huazhong Univ ence Technol 2013; 33:680-686.
15. Zou YR, Zhang J, Wang J, Peng L, Li GS, Wang L, et al. Erythropoietin receptor activation protects the kidney from ischemia/reperfusion-induced apoptosis by activating erk/p53 signal pathway. Transplant Proc 2016; 48:217-221.
16. Borges MC, Martini LA, Rogero MM. Current perspectives on vitamin D, immune system, and chronic diseases. Nutrition 2011; 27:399-404.
17. Assalin HB, Rafacho BP, Santos PPD, Ardisson LP, Roscani MG, Chiuso-Minicucci F, et al. Impact of the length of vitamin D deficiency on cardiac remodeling. Circ Heart Fail 2013; 6:809-816.
18. Danik JS, Manson JAE. Vitamin D and cardiovascular disease. Curr Treat Options Cardiovasc Med 2012; 14:414-424.
19. Braun AB, Gibbons FK, Litonjua AA, Giovannucci E, Christopher KB. Low serum 25-hydroxyvitamin D at critical care initiation is associated with increased mortality. Crit Care Med 2012; 40: 63-72.
20. Sassi F, Tamone C, D’Amelio P. Vitamin D: nutrient, hormone, and immunomodulator. Nutrients 2018; 10:1656-1670.
21. Baeke F, Etten EV, Overbergh L, Mathieu C. Vitamin D3 and the immune system: maintaining the balance in health and disease. Nut Res Rev 2007; 20:106-118.
22. De Haes P, Garmyn M, Degreef H, Vantieghem K, Bouillon R, Segaert S. 1,25-Dihydroxyvitamin D3 inhibits ultraviolet B-induced apoptosis, Jun kinase activation, and interleukin-6 production in primary human keratinocytes. J Cell Biochem 2003; 89:663-673.
23. Loiola RA, Fernandes L, Eichler R, Passaglia Rde C, Fortes ZB, de Carvalho MH. Vascular mechanisms involved in angiotensin II-induced venoconstriction in hypertensive rats. Peptides 2011; 32:2116-2121.
24. Mehta RL, Cerdá J, Burdmann EA, Tonelli M, García-García G, Jha V, et al. International society of nephrology’s 0by25 initiative for acute kidney injury (zero preventable deaths by 2025): a human rights case for nephrology. Lancet 2015; 385:2616-2643.
25. Lewington AJ, Cerdá J, Mehta RL. Raising awareness of acute kidney injury: a global perspective of a silent killer. Kidney Int 2013; 84:457-467.
26. Kellum JA, Lameire N, KDIGO AKI Guideline Work Group. Diagnosis, evaluation, and management of acute kidney injury: a KDIGO summary (Part 1). Crit Care 2013; 17:204-219.
27. Lameire NH, Bagga A, Cruz D, De Maeseneer J, Endre Z, Kellum JA, et al. Acute kidney injury: an increasing global concern. Lancet 2013; 382:170-179.
28. Kashani K, Shao M, Li G, Williams AW, Rule AD, Kremers WK, et al. No increase in the incidence of acute kidney injury in a population-based annual temporal trends epidemiology study. Kidney Int 2017; 92:721-728.
29. Chen X, Wang CC, Song SM, Wei SY, Li JS, Zhao SL, et al. The administration of erythropoietin attenuates kidney injury induced by ischemia/reperfusion with increased activation of Wnt/β-catenin signaling. J Formos Med Assoc 2015; 114:430-437.
30. Zhang J, Zhao D, Na N, Li H, Miao B, Hong L, et al. Renoprotective effect of erythropoietin via modulation of the STAT6/MAPK/NF-κB pathway in ischemia/reperfusion injury after renal transplantation. Int J Mol Med 2018; 41:25-32.
31. Kapil A, Singh JP, Kaur T, Singh B, Singh AP. Involvement of peroxisome proliferator-activated receptor gamma in vitamin D-mediated protection against acute kidney injury in rats. J Surg Res 2013; 185:774-783.
32. Kim YO, Li C, Sun BK, Kim JS, Lim SW, Choi BS, et al. Preconditioning with 1,25-dihydroxyvitamin D3 protects against subsequent ischemia-reperfusion injury in the rat kidney. Nephron 2005; 100:85-94.
33. Jean G, Souberbielle JC, Chazot C. Vitamin D in chronic kidney disease and dialysis patients. Nutrients 2017; 9:328-343.
34. Shi M, Flores B, Li P, Gillings N, McMillan KL, Ye J, et al. Effects of erythropoietin receptor activity on angiogenesis, tubular injury, and fibrosis in acute kidney injury: a “U-shaped” relationship. Am J Physiol Renal Physiol 2018; 314:501-516.
35. Jelkmann W, Hellwig-Bürgel T. Biology of erythropoietin. Adv Exp Med Biol 2001; 502:169-187.
36. Johnson DW, Pat B, Vesey DA, Guan Z, Endre Z, Gobe GC. Delayed administration of darbepoetin or erythropoietin protects against ischemic acute renal injury and failure. Kidney Int 2006; 69:1806-1813.
37. Icardi A, Paoletti E, De Nicola L, Mazzaferro S, Russo R, Cozzolino M. Renal anaemia and EPO hyporesponsiveness associated with vitamin D deficiency: the potential role of inflammation. Nephrol Dial Transplant 2013; 28:1672-1679.
38. Seif AA, Abdelwahed DM. Vitamin D ameliorates hepatic ischemic/reperfusion injury in rats. J Physiol Biochem 2014; 70:659-666.
39. Quraishi SA, De Pascale G, Needleman JS, Nakazawa H, Kaneki M, Bajwa EK, et al. Effect of cholecalciferol supplementation on vitamin d status and cathelicidin levels in sepsis: a randomized, placebo-controlled trial. Crit Care Med 2015; 43:1928-1937.
40. Wang X, Zhu Y, Wang X, Yang Y, Cheng S. Cardioprotective effect of calcitriol on myocardial injury induced by isoproterenol in rats. J Cardiovasc Pharmacol Ther 2013; 18:386-391.
41. Aoshiba K, Onizawa S, Tsuji T, Nagai A. Therapeutic effects of erythropoietin in murine models of endotoxin shock. Crit Care Med 2009; 37:889-898.
42. Sharples EJ, Patel N, Brown P, Stewart K, Mota-Philipe H, Sheaff M, et al. Erythropoietin protects the kidney against the injury and dysfunction caused by ischemia-reperfusion. J Am Soc Nephrol 2004; 15:2115-2124.
43. Yang CW, Li C, Jung JY, Shin SJ, Choi BS, Lim SW, et al. Preconditioning with erythropoietin protects against subsequent ischemia-reperfusion injury in rat kidney. FASEB J 2003; 17:1754-1755.
44. Alon DB, Chaimovitz C, Dvilansky A, Lugassy G, Douvdevani A, Shany S, et al. Novel role of 1,25(OH)(2)D(3) in induction of erythroid progenitor cell proliferation. Exp Hematol 2002; 30: 403-409.
45. Aucella F, Scalzulli RP, Gatta G, Vigilante M, Carella AM, Stallone C. Calcitriol increases burst-forming unit-erythroid proliferation in chronic renal failure. A synergistic effect with r-HuEpo. Nephron Clin Pract 2003; 95:121-127.
46. Santoro D, Caccamo D, Lucisano S, Buemi M, Sebekova K, Teta D, et al. Interplay of vitamin D, erythropoiesis, and the renin-angiotensin system. Biomed Res Int 2015; 2015:145828-145839.
Iranian Journal of Basic Medical Sciences
Volume 24, Issue 2
February 2021
Pages 167-174

Files

Share

How to cite

Statistics