22-oxacalcitriol prevents acute kidney injury via inhibition of apoptosis and enhancement of autophagy
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The pathophysiology of ischemic acute kidney injury (AKI) is thought to include a complex interplay between tubular cell damage and regeneration. Several lines of evidences suggest a potential renoprotective effect of vitamin D. In this study, we investigated the effect of 22-oxacalcitriol (OCT), a synthetic vitamin D analogue, on renal fate in a rat model of ischemia reperfusion injury (IRI) induced acute kidney injury (AKI).
22-oxacalcitriol (OCT) was administered via intraperitoneal (IP) injection before ischemia, and continued after IRI that was performed through bilateral clamping of the renal pedicles. 96 h after reperfusion, rats were sacrificed for the evaluation of autophagy, apoptosis, and cell cycle arrest. Additionally, assessments of toll-like receptors (TLR), interferon gamma (IFN-g) and sodium–hydrogen exchanger-1 (NHE-1) were also performed to examine their relations to OCT-mediated cell response.
Treatment with OCT-attenuated functional deterioration and histological damage in IRI induced AKI, and significantly decreased cell apoptosis and fibrosis. In comparison with IRI rats, OCT + IRI rats manifested a significant exacerbation of autophagy as well as reduced cell cycle arrest. Moreover, the administration of OCT decreased IRI-induced upregulation of TLR4, IFN-g and NHE-1.
These results demonstrate that treatment with OCT has a renoprotective effect in ischemic AKI, possibly by suppressing cell loss. Changes in the expression of IFN-g and NHE-1 could partially link OCT to the cell survival-promoted effects.
KeywordsAcute kidney injury Ischemia reperfusion injury Vitamin D Autophagy Sodium–hydrogen exchanger Apoptosis
The skillful technical assistance of Afaf, Aza and Tarek is appreciated. This work was supported by research Grants from the Faculty of Medicine, Cairo University.
MH, SAAG and NS carried out the study design and performed the analysis. LR, MAM and SAAG carried out studies recruitment and data extraction. NS, SAAG and MH participated in study qualifications. All authors helped to draft the manuscript.
Compliance with ethical standards
Conflict of interest
All the authors have declared no competing interest.
- 1.Duann P, Lianos E, Ma J, Lin P-H. Autophagy, innate immunity and tissue repair in acute kidney injury. Int J Mol Sci [Internet]. 2016 [cited 2017 Jun 12];17:662. http://www.ncbi.nlm.nih.gov/pubmed/27153058.
- 3.Sun L, Shen Y-L, Liu H-J, Hu Y-J, Kang Y-L, Huang W-Y. The expression of response gene to complement 32 on renal ischemia reperfusion injury in rat. Ren Fail. 2016;38:276–81.Google Scholar
- 4.Havasi A, Borkan SC. Apoptosis and acute kidney injury. Kidney Int [Internet]. NIH Public Access; 2011 [cited 2017 Jun 12];80:29–40. Available from: http://www.ncbi.nlm.nih.gov/pubmed/21562469.
- 5.Reumann S, Shogren KL, Yaszemski MJ, Maran A. Inhibition of autophagy increases 2-methoxyestradiol-induced cytotoxicity in SW1353 chondrosarcoma cells. J Cell Biochem [Internet]. 2016 [cited 2017 Jun 12];117:751–9. Available from: http://www.ncbi.nlm.nih.gov/pubmed/26335692.
- 6.Mei S, Livingston M, Hao J, Li L, Mei C, Dong Z. Autophagy is activated to protect against endotoxic acute kidney injury. Sci Rep [Internet]. 2016 [cited 2017 Jun 12];6:22171. Available from: http://www.nature.com/articles/srep22171.
- 7.Horie R, Nakamura O, Yamagami Y, Mori M, Nishimura H, Fukuoka N, et al. Apoptosis and antitumor effects induced by the combination of an mTOR inhibitor and an autophagy inhibitor in human osteosarcoma MG63 cells. Int J Oncol [Internet]. 2015 [cited 2017 Jun 12];48:37–44. Available from: http://www.ncbi.nlm.nih.gov/pubmed/26530936.
- 9.Bajwa A, Huang L, Kurmaeva E, Ye H, Dondeti KR, Chroscicki P, et al. Sphingosine kinase 2 deficiency attenuates kidney fibrosis via IFN-γ. J Am Soc Nephrol [Internet]. 2017 [cited 2017 Jun 12];28:1145–61. Available from: http://www.ncbi.nlm.nih.gov/pubmed/27799486.
- 10.Wu C-J, Sheu J-R, Chen H-H, Liao H-F, Yang Y-C, Yang S, et al. Modulation of monocyte-derived dendritic cell differentiation is associated with ischemic acute renal failure. J Surg Res [Internet]. 2006 [cited 2017 Jun 12];132:104–11. Available from: http://www.ncbi.nlm.nih.gov/pubmed/16330051.
- 11.Wang Q, Su Y, Li Y, Zhang Y, Yang S, Wang J, et al. Atorvastatin alleviates renal ischemia-reperfusion injury in rats by promoting M1-M2 transition. Mol Med Rep [Internet]. 2016 [cited 2017 Jun 12];15:798–804. Available from: http://www.ncbi.nlm.nih.gov/pubmed/28035383.
- 12.Li L, Huang L, Sung SJ, Lobo PI, Brown MG, Gregg RK, et al. NKT cell activation mediates neutrophil IFN-gamma production and renal ischemia-reperfusion injury. J Immunol [Internet]. 2007 [cited 2017 Jun 13];178:5899–911. Available from: http://www.ncbi.nlm.nih.gov/pubmed/17442974.
- 13.Li L, Huang L, Vergis AL, Ye H, Bajwa A, Narayan V, et al. IL-17 produced by neutrophils regulates IFN-γ-mediated neutrophil migration in mouse kidney ischemia-reperfusion injury. J Clin Invest [Internet]. 2010 [cited 2017 Jun 13];120:331–42. Available from: http://www.ncbi.nlm.nih.gov/pubmed/20038794.
- 14.Roedder S, Kimura N, Okamura H, Hsieh S-C, Gong Y, Sarwal MM. Significance and suppression of redundant IL17 responses in acute allograft rejection by bioinformatics based drug repositioning of fenofibrate. PLoS One [Internet]. Public Library of Science; 2013 [cited 2017 Jun 13];8:e56657. Available from: http://www.ncbi.nlm.nih.gov/pubmed/23437201.
- 15.Annunziato L. New strategies in stroke intervention ionic transporters, pumps, and new channels [Internet]. springer; 2009. Available from: https://books.google.com.eg/books?id=R7SVsgD6-tEC&printsec=frontcover&dq=New+Strategies+in+Stroke+Intervention+Ionic+Transporters,+Pumps,+and+New+Channels&hl=en&sa=X&ved=0ahUKEwjBla7Ru8fUAhXGbRQKHWpCBbQQ6AEIJjAA#v=onepage&q=New Strategies in Stroke Interv.
- 16.Huhtakangas JA, Veijola J, Turunen S, Karjalainen A, Valkealahti M, Nousiainen T, et al. 1,25(OH)2D3 and calcipotriol, its hypocalcemic analog, exert a long-lasting anti-inflammatory and anti-proliferative effect in synoviocytes cultured from patients with rheumatoid arthritis and osteoarthritis. J Steroid Biochem Mol Biol [Internet]. 2017 [cited 2017 Jun 12]; Available from: http://linkinghub.elsevier.com/retrieve/pii/S0960076017300171.
- 17.Braun AB, Litonjua AA, Moromizato T, Gibbons FK, Giovannucci E, Christopher KB. Association of low serum 25-hydroxyvitamin D levels and acute kidney injury in the critically ill. Crit Care Med [Internet]. 2012 [cited 2017 Jun 13];40:3170–9. Available from: http://www.ncbi.nlm.nih.gov/pubmed/22975885.
- 18.Braun AB, Christopher KB. Vitamin D in acute kidney injury. Inflamm Allergy Drug Targets [Internet]. 2013 [cited 2017 Jun 13];12:262–72. Available from: http://www.ncbi.nlm.nih.gov/pubmed/23782211.
- 19.de Boer IH, Katz R, Chonchol M, Ix JH, Sarnak MJ, Shlipak MG, et al. Serum 25-hydroxyvitamin D and change in estimated glomerular filtration rate. Clin J Am Soc Nephrol [Internet]. 2011 [cited 2017 Jun 13];6:2141–9. Available from: http://www.ncbi.nlm.nih.gov/pubmed/21836148.
- 20.de Bragança AC, Volpini RA, Mehrotra P, Andrade L, Basile DP. Vitamin D deficiency contributes to vascular damage in sustained ischemic acute kidney injury. Physiol Rep [Internet]. 2016 [cited 2017 Jun 12];4:e12829. Available from: http://physreports.physiology.org/lookup/doi/ https://doi.org/10.14814/phy2.12829.
- 24.Rogers NM, Stephenson MD, Kitching AR, Horowitz JD, Coates PTH. Amelioration of renal ischaemia-reperfusion injury by liposomal delivery of curcumin to renal tubular epithelial and antigen-presenting cells. Br J Pharmacol [Internet]. 2012 [cited 2017 Jun 14];166:194–209. Available from: http://doi.wiley.com/https://doi.org/10.1111/j.1476-5381.2011.01590.x.
- 25.Khowailed A, Sandra Younan M, Ashour H, Abd Kamel E, et al. Effects of ghrelin on sepsis-induced acute kidney injury: one step forward. Clin Exp Nephrol [Internet]. 2014 [cited 2018 Jan 22]; Available from: https://link.springer.com/content/pdf/10.1007/s10157-014-1006-x.pdf.
- 26.Grabulosa CC, Batista MC, Cendoroglo M, Quinto BMR, Narciso R, Monte JC, et al. Frequency of TGF-β and IFN-γ genotype as risk factors for acute kidney injury and death in intensive care unit patients. Biomed Res Int [Internet]. Hindawi Publishing Corporation; 2014 [cited 2017 Jun 12];2014:904730. Available from: http://www.ncbi.nlm.nih.gov/pubmed/25147823.
- 27.Karimi MH, Daneshmandi S, Pourfathollah AA, Geramizadeh B, Yaghobi R, Rais-Jalali GA, et al. A study of the impact of cytokine gene polymorphism in acute rejection of renal transplant recipients. Mol Biol Rep [Internet]. 2012 [cited 2017 Jun 12];39:509–15. Available from: http://www.ncbi.nlm.nih.gov/pubmed/21562768.
- 28.García-Sánchez O, López-Novoa JM, López-Hernández FJ. Interferon-γ reduces the proliferation of primed human renal tubular cells. Nephron Extra [Internet]. Karger Publishers; 2014 [cited 2017 Jun 12];4:1–7. Available from: http://www.ncbi.nlm.nih.gov/pubmed/24575118.
- 29.Holthouser KA, Mandal A, Merchant ML, Schelling JR, Delamere NA, Valdes RR, et al. Ouabain stimulates Na-K-ATPase through a sodium/hydrogen exchanger-1 (NHE-1)-dependent mechanism in human kidney proximal tubule cells. Am J Physiol Renal Physiol [Internet]. American Physiological Society; 2010 [cited 2017 Jun 15];299:F77–90. Available from: http://www.ncbi.nlm.nih.gov/pubmed/20427472.
- 30.Kapitsinou PP, Haase VH. Molecular mechanisms of ischemic preconditioning in the kidney. Am J Physiol Renal Physiol [Internet]. American Physiological Society; 2015 [cited 2017 Jun 15];309:F821–34. Available from: http://www.ncbi.nlm.nih.gov/pubmed/26311114.
- 31.Guan X, Qian Y, Shen Y, Zhang L, Du Y, Dai H, et al. Autophagy protects renal tubular cells against ischemia / reperfusion injury in a time-dependent manner. Cell Physiol Biochem [Internet]. 2015 [cited 2017 Jun 15];36:285–98. Available from: http://www.karger.com/?doi=10.1159/000374071.
- 32.Mariño G, Niso-Santano M, Baehrecke EH, Kroemer G. Self-consumption: the interplay of autophagy and apoptosis. Nat Rev Mol Cell Biol [Internet]. 2014 [cited 2017 Jun 15];15:81–94. Available from: http://www.nature.com/doifinder/https://doi.org/10.1038/nrm3735.
- 33.Hou W, Han J, Lu C, Goldstein LA, Rabinowich H. Autophagic degradation of active caspase-8: a crosstalk mechanism between autophagy and apoptosis. Autophagy [Internet]. 2010 [cited 2017 Jun 15];6:891–900. Available from: http://www.tandfonline.com/doi/abs/https://doi.org/10.4161/auto.6.7.13038.
- 34.Mari?o G, Niso-Santano M, Baehrecke EH, Kroemer G. Self-consumption: the interplay of autophagy and apoptosis. Nat Rev Mol Cell Biol [Internet]. 2014 [cited 2017 Jun 15];15:81–94. Available from: http://www.nature.com/doifinder/https://doi.org/10.1038/nrm3735.
- 35.Maiuri MC, Zalckvar E, Kimchi A, Kroemer G. Self-eating and self-killing: crosstalk between autophagy and apoptosis. Nat Rev Mol Cell Biol [Internet]. 2007 [cited 2017 Jun 15];8:741–52. Available from: http://www.ncbi.nlm.nih.gov/pubmed/17717517.
- 36.Wu H-H, Hsiao T-Y, Chien C-T, Lai M-K. Ischemic conditioning by short periods of reperfusion attenuates renal ischemia/reperfusion induced apoptosis and autophagy in the rat. J Biomed Sci [Internet]. 2009 [cited 2017 Jun 14];16:19. Available from: http://www.ncbi.nlm.nih.gov/pubmed/19272187.
- 37.Wu S, Sun J. Vitamin D. vitamin D receptor, and macroautophagy in inflammation and infection. Discov Med [Internet]. 2011 [cited 2017 Jun 14];11:325–35. Available from: http://www.ncbi.nlm.nih.gov/pubmed/21524386.
- 38.An CH, Wang XM, Lam HC, Ifedigbo E, Washko GR, Ryter SW, et al. TLR4 deficiency promotes autophagy during cigarette smoke-induced pulmonary emphysema. Am J Physiol Lung Cell Mol Physiol [Internet]. 2012 [cited 2017 Jun 15];303:L748–57. Available from: http://ajplung.physiology.org/cgi/doi/https://doi.org/10.1152/ajplung.00102.2012.
- 39.Chang Y-P, Tsai C-C, Huang W-C, Wang C-Y, Chen C-L, Lin Y-S, et al. Autophagy facilitates IFN-gamma-induced Jak2-STAT1 activation and cellular inflammation. J Biol Chem [Internet]. American Society for Biochemistry and Molecular Biology; 2010 [cited 2017 Jun 15];285:28715–22. Available from: http://www.ncbi.nlm.nih.gov/pubmed/20592027.
- 40.Ghadimi D, de Vrese M, Heller KJ, Schrezenmeir J. Lactic acid bacteria enhance autophagic ability of mononuclear phagocytes by increasing Th1 autophagy-promoting cytokine (IFN-γ) and nitric oxide (NO) levels and reducing Th2 autophagy-restraining cytokines (IL-4 and IL-13) in response to Mycobacterium tuberculosis antigen. Int Immunopharmacol [Internet]. 2010 [cited 2017 Jun 15];10:694–706. Available from: http://www.ncbi.nlm.nih.gov/pubmed/20381647.
- 41.Garcia AG, Wilson RM, Heo J, Murthy NR, Baid S, Ouchi N, et al. Interferon-γ ablation exacerbates myocardial hypertrophy in diastolic heart failure. Am J Physiol Heart Circ Physiol [Internet]. American Physiological Society; 2012 [cited 2017 Jun 18];303:H587–96. Available from: http://www.ncbi.nlm.nih.gov/pubmed/22730392.
- 42.Okuda S, Tamaki K, Ando T, Nagashima A, Nakayama M, Fukuda K, et al. Increased expression of Na+/H+ exchanger in the injured renal tissues of focal glomerulosclerosis in rats. Kidney Int [Internet]. 1994 [cited 2017 Jun 18];46:1635–43. Available from: http://linkinghub.elsevier.com/retrieve/pii/S0085253815587449.
- 43.Yu H, Freedman BI, Rich SS, Bowden DW. Human Na+/H + exchanger genes: identification of polymorphisms by radiation hybrid mapping and analysis of linkage in end-stage renal disease. Hypertens (Dallas, Tex 1979) [Internet]. 2000 [cited 2017 May 31];35:135–43. Available from: http://www.ncbi.nlm.nih.gov/pubmed/10642288.
- 44.Li P, Chen G-R, Wang F, Xu P, Liu L-Y, Yin Y-L, et al. Inhibition of NA+/H+ exchanger 1 attenuates renal dysfunction induced by advanced glycation end products in rats. J Diabetes Res [Internet]. Hindawi Publishing Corporation; 2016 [cited 2017 Jun 18];2016:1–10. Available from: http://www.hindawi.com/journals/jdr/2016/1802036/.
- 45.Togashi K, Wakatsuki S, Furuno A, Tokunaga S, Nagai Y, Araki T. Na+/H+ exchangers induce autophagy in neurons and inhibit polyglutamine-induced aggregate formation. Arakawa H, editor. PLoS One [Internet]. 2013 [cited 2017 May 31];8:e81313. Available from: http://dx.plos.org/https://doi.org/10.1371/journal.pone.0081313.
- 46.Lagadic-Gossmann D, Huc L, Lecureur V. Alterations of intracellular pH homeostasis in apoptosis: origins and roles. Cell Death Differ [Internet]. 2004 [cited 2017 Jun 5];11:953–61. Available from: http://www.ncbi.nlm.nih.gov/pubmed/15195071.
- 47.Inda Filho AJ, Melamed ML. Vitamin D and kidney disease. What we know and what we do not know. J Bras Nefrol [Internet]. 2013 [cited 2017 Jun 15];35:323–31. Available from: http://www.ncbi.nlm.nih.gov/pubmed/24402112.
- 48.de Bragança AC, Volpini RA, Canale D, Gonçalves JG, Shimizu MHM, Sanches TR, et al. Vitamin D deficiency aggravates ischemic acute kidney injury in rats. Physiol Rep [Internet]. Wiley-Blackwell; 2015 [cited 2017 Jun 15];3. Available from: http://www.ncbi.nlm.nih.gov/pubmed/25780095.
- 49.Lai L, Qian J, Yang Y, Xie Q, You H, Zhou Y, et al. Is the serum vitamin D level at the time of hospital-acquired acute kidney injury diagnosis associated with prognosis? Burdmann EA, editor. PLoS One [Internet]. Public Library of Science; 2013 [cited 2017 Jun 15];8:e64964. Available from: http://dx.plos.org/https://doi.org/10.1371/journal.pone.0064964.
- 50.Williams S, Malatesta K, Norris K. Vitamin D and chronic kidney disease. Ethn Dis [Internet]. NIH Public Access; 2009 [cited 2017 Jun 15];19:S5–8–11. Available from: http://www.ncbi.nlm.nih.gov/pubmed/20077598.
- 51.Adişen E, Gülekon A, Erdem O, Dursun A, Gürer MA. The effects of calcipotriol and methylprednisolone aseponate on bcl-2, p53 and ki-67 expression in psoriasis. J Eur Acad Dermatol Venereol [Internet]. 2006 [cited 2017 Jun 14];20:527–33. Available from: http://doi.wiley.com/https://doi.org/10.1111/j.1468-3083.2006.01508.x.
- 52.Wagner N, Wagner K-D, Schley G, Badiali L, Theres H, Scholz H. 1,25-dihydroxyvitamin D3-induced apoptosis of retinoblastoma cells is associated with reciprocal changes of Bcl-2 and bax. Exp Eye Res [Internet]. 2003 [cited 2017 Jun 14];77:1–9. Available from: http://www.ncbi.nlm.nih.gov/pubmed/12823982.
- 53.Jeong MS, Kim J-Y, Lee HI, Seo SJ. Calcitriol may down-regulate mRNA over-expression of toll-like receptor-2 and -4, LL-37 and proinflammatory cytokines in cultured human keratinocytes. Ann Dermatol [Internet]. 2014 [cited 2017 Jun 18];26:296. Available from: http://www.ncbi.nlm.nih.gov/pubmed/24966627.
- 54.Gorman S, Judge MA, Hart PH. Gene regulation by 1,25-dihydroxyvitamin D3 in CD4+ CD25+ cells is enabled by IL-2. J Invest Dermatol [Internet]. 2010 [cited 2017 Jun 18];130:2368–76. Available from: http://www.ncbi.nlm.nih.gov/pubmed/20574434.
- 55.Park JW, Bae EH, Kim IJ, Ma SK, Choi C, Lee J, et al. Renoprotective effects of paricalcitol on gentamicin-induced kidney injury in rats. AJP Ren Physiol [Internet]. 2010 [cited 2017 Jun 18];298:F301–13. Available from: http://www.ncbi.nlm.nih.gov/pubmed/19940033.
- 56.Lee J-W, Kim SC, Ko YS, Lee HY, Cho E, Kim M-G, et al. Renoprotective effect of paricalcitol via a modulation of the TLR4-NF-κB pathway in ischemia/reperfusion-induced acute kidney injury. Biochem Biophys Res Commun [Internet]. 2014 [cited 2017 Jun 14];444:121–7. Available from: http://linkinghub.elsevier.com/retrieve/pii/S0006291X14000205.
- 57.Do JE, Kwon SY, Park S, Lee E-S. Effects of vitamin D on expression of Toll-like receptors of monocytes from patients with Behct’s disease. [cited 2017 Jun 18]; Available from: https://pdfs.semanticscholar.org/fcc9/93b9e23b941a56cf285f0973b6a63f0b1adf.pdf.
- 58.Gill R, Nazir TM, Wali R, Sitrin M, Brasitus TA, Ramaswamy K, et al. Regulation of rat ileal NHE3 by 1,25(OH)2-vitamin D3. Dig Dis Sci [Internet]. 2002 [cited 2017 Jun 18];47:1169–74. Available from: http://www.ncbi.nlm.nih.gov/pubmed/12018917.
- 59.Shao Y, Lv C, Yuan Q, Wang Q. Levels of Serum 25(OH)VD3, HIF-1α, VEGF, vWf, and IGF-1 and their correlation in type 2 diabetes patients with different urine albumin creatinine ratio. J Diabetes Res [Internet]. 2016 [cited 2017 Jun 18];2016:1–7. Available from: http://www.ncbi.nlm.nih.gov/pubmed/27069929.
- 61.Yang W, Wang H, Fliegel L. Regulation of Na role of a novel poly(dA∙dT) element in regulation of the NHE1 promoter. [cited 2017 Jun 18]; Available from: http://www.jbc.org/content/271/34/20444.full.pdf.
- 62.Miya M, Maeshima A, Mishima K, Sakurai N, Ikeuchi H, Kuroiwa T, et al. Enhancement of in vitro human tubulogenesis by endothelial cell-derived factors: implications for in vivo tubular regeneration after injury. Am J Physiol Ren Physiol [Internet]. 2011 [cited 2017 Jun 19];301. Available from: http://ajprenal.physiology.org/content/301/2/F387.long.
- 63.Kashani K, Al-Khafaji A, Ardiles T, Artigas A, Bagshaw SM, Bell M, et al. Discovery and validation of cell cycle arrest biomarkers in human acute kidney injury. Crit Care [Internet]. BioMed Central; 2013 [cited 2017 Jun 19];17:R25. Available from: http://www.ncbi.nlm.nih.gov/pubmed/23388612.
- 64.Alge JL, Arthur JM. Biomarkers of AKI: a review of mechanistic relevance and potential therapeutic implications. Clin J Am Soc Nephrol [Internet]. American Society of Nephrology; 2015 [cited 2017 Jun 19];10:147–55. Available from: http://www.ncbi.nlm.nih.gov/pubmed/25092601.
- 65.Koyner JL, Shaw AD, Chawla LS, Hoste EAJ, Bihorac A, Kashani K, et al. Tissue inhibitor metalloproteinase-2 (TIMP-2)⋅IGF-binding protein-7 (IGFBP7) levels are associated with adverse long-term outcomes in patients with AKI. J Am Soc Nephrol [Internet]. American Society of Nephrology; 2015 [cited 2017 Jun 19];26:1747–54. Available from: http://www.ncbi.nlm.nih.gov/pubmed/25535301.
- 66.Peng Z-Y, Zhou F, Kellum JA. Cross-species validation of cell cycle arrest markers for acute kidney injury in the rat during sepsis. Intensive care Med Exp [Internet]. Springer; 2016 [cited 2017 May 11];4:12. Available from: http://www.ncbi.nlm.nih.gov/pubmed/27245788.
- 67.Wang Z, Famulski K, Lee J, Das SK, Wang X, Halloran P, et al. TIMP2 and TIMP3 have divergent roles in early renal tubulointerstitial injury. Kidney Int [Internet]. 2014 [cited 2017 Jun 19];85:82–93. Available from: http://linkinghub.elsevier.com/retrieve/pii/S0085253815561346.
- 68.Bao B-Y, Yeh S-D, Lee Y-F. 1α,25-dihydroxyvitamin D3 inhibits prostate cancer cell invasion via modulation of selective proteases. Carcinogenesis [Internet]. 2005 [cited 2017 Jun 19];27:32–42. Available from: http://www.ncbi.nlm.nih.gov/pubmed/15987715.
- 69.Koli K, Keski-Oja J. 1α,25-dihydroxyvitamin D3 and its analogues down-regulate cell invasion-associated proteases in cultured malignant cells. Cell Growth Differ [Internet]. 2000 [cited 2017 Jun 19];11:221–9. Available from: http://www.ncbi.nlm.nih.gov/pubmed/10775039.
- 70.Swami S, Raghavachari N, Muller UR, Bao YP, Feldman D. Vitamin D growth inhibition of breast cancer cells: gene expression patterns assessed by cDNA microarray. Breast Cancer Res Treat [Internet]. 2003 [cited 2017 Jun 19];80:49–62. Available from: http://www.ncbi.nlm.nih.gov/pubmed/12889598.