Low Expression of Calcitriol Level and Interleukin-10 and Hypoxia-inducible Factor-1 Alpha Expression on Placenta

I Ketut Suwiyoga; I Nyoman Mantik Astawa; I Made Jawi; I Wayan Artana Putra

doi:10.3889/oamjms.2023.11213

Authors

I Ketut Suwiyoga Department of Obstetrics and Gynecology, Faculty of Medicine, University of Udayana, Prof. Dr. I. G. N. G. Ngoerah Hospital, Bali, Indonesia
I Nyoman Mantik Astawa Department of Obstetrics and Gynecology, Faculty of Medicine, University of Udayana, Prof. Dr. I. G. N. G. Ngoerah Hospital, Bali, Indonesia
I Made Jawi Department of Obstetrics and Gynecology, Faculty of Medicine, University of Udayana, Prof. Dr. I. G. N. G. Ngoerah Hospital, Bali, Indonesia
I Wayan Artana Putra Department of Obstetrics and Gynecology, Faculty of Medicine, University of Udayana, Prof. Dr. I. G. N. G. Ngoerah Hospital, Bali, Indonesia

DOI:

https://doi.org/10.3889/oamjms.2023.11213

Keywords:

High HIF-1α, Calcitriol, IL-10, Preeclampsia

Abstract

BACKGROUND: Preeclampsia (PE) is the disease of theories and the second leading cause of maternal and perinatal morbidities and mortalities worldwide. These pathological disturbances will induce inflammation process, oxidative stress, and poor subsequent growth on the fetus including 32% of intrauterine growth restriction, 22% of prematurity, and 24% of neonatal sepsis and asphyxia. There are many theories about the mechanism of PE. In the molecularly level, it is suspected that the low level of calcitriol and interleukin (IL)-10 expressions and high expression of hypoxia- inducible factor (HIF)-1α are the risk factors of PE.

AIM: The aim of this study was to prove the low calcitriol level, IL-10, and high expression of HIF-1α in the placenta as the risk factors of PE.

METHODS: A nested case–control study was conducted at the Department of Obstetrics-Gynecology Sanglah and Wangaya Hospital Denpasar, Bali, from November 2020 to February 2021.

RESULTS: A total of 64 samples of 20–40 weeks gestation age were selected by purposive consecutive sampling, divided into two groups consist of 32 PE as the cases and 32 non-PE as the controls. The material examination, 3 × 3 cm was isolated from the maternal placental surface, was performed at Laboratorium Biomedik Terpadu, Faculty of Medicine, Udayana University. We performed an ELISA technique to find out the calcitriol level; in the other hand, we used immunohistochemistry for detected expression of IL-10 and HIF-1-α. The results revealed the risk of PE in low placental calcitriol levels about 13.8 times higher than in high calcitriol levels (odds ratio [OR] = 13,801, 95% confidence interval [CI] = 4.048–47,050, p = 0.001. The risk of PE in low placental IL-10 expression about 6.6 times higher than in high IL-10 expression (OR = 6600; 95% CI = 2208–19,728; p = 0.001). The risk of PE in high placental HIF-1-α expression about 5.6 times higher than in low placental HIF-1-α expression (OR = 5.622; 95% CI = 1.922–16.450; p = 0.001).

CONCLUSION: Low calcitriol level, low IL-10, and high HIF-1-α expression on the placenta were proved as significant risk factors for the development of PE.

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References

Abalos E, Cuesta C, Grosso AL, Chou D, Say L. Global and regional estimates of preeclampsia and eclampsia: A systematic review. Eur J Obstet Gynecol Reprod Biol. 2013;170(1):1-7. https://doi.org/10.1016/j.ejogrb.2013.05.005 PMid:23746796 DOI: https://doi.org/10.1016/j.ejogrb.2013.05.005

Ananth CV, Keyes KM, Wapner RJ. Pre-eclampsia rates in the United States, 1980-2010: Age-period-cohort analysis. BMJ. 2013;347:f6564. https://doi.org/10.1136/bmj.f6564 PMid:24201165 DOI: https://doi.org/10.1136/bmj.f6564

Osungbade KO, Ige OK. Public health perspectives of preeclampsia in developing countries: Implication for health system strengthening. J Pregnancy. 2011;2011:481095. https://doi.org/10.1155/2011/481095 PMid:21547090 DOI: https://doi.org/10.1155/2011/481095

Warouw PC, Suparman E, Wagey FW. Preeclampsia characteristics in Prof. Dr. R. D. Kandou Hospital, Manado. J e-Clinic. 2016;4(1):375-9. DOI: https://doi.org/10.35790/ecl.4.1.2016.10986

Lidapraja HS, Kusuma AA, Suwiyoga K. Perbedaan Kadar Serum F2 Iso Prostane Pada Pre-eklampsia Dan Kehamilan Normal. Thesis; 2013.

Bokhari ZH, Yasoob M, Intesar A, Haq MF. Neonatal outcome in patients with preeclampsia. Pak J Med Sci. 2014;8(4):970-2.

McKenzie KA, Trotman H. A retrospective study of neonatal outcome in preeclampsia at the university hospital of the West Indies: A resource-limited setting. J Trop Pediatr. 2019;65(1):78-83. https://doi.org/10.1093/tropej/fmy014 PMid:29590467 DOI: https://doi.org/10.1093/tropej/fmy014

Cunningham FG, Leveno KJ, Bloom SL, Hauth JC, Rouse DJ, Spong CY. Williams Obstetrics. 25th ed. New York: McGraw-Hill Education; 2018.

Hernawati I. Analisis Kematian Ibu di Indonesia Tahun 2010 Berdasarkan Data SDKI, Riskesdas dan Laporan Rutin KIA; 2011.

Kanagal DV, Rajesh A, Rao K, Shetty H, Shetty PK, Ullal H. Zinc and copper levels in preeclampsia: A study from coastal South India. Int J Reprod Contracept Obstet Gynecol. 2014;3(2):370-3. https://doi.org/10.5455/2320-1770.ijrcog20140617 DOI: https://doi.org/10.5455/2320-1770.ijrcog20140617

Elind AH. Trace elements as potential biomarkers of preeclampsia. Ann Res Rev Biol. 2016;9(1):1-10. https://doi.org/10.9734/arrb/2016/20342 DOI: https://doi.org/10.9734/ARRB/2016/20342

Verburg PE, Dekker GA, Tucker G, Scheil W, Erwich JJ, Roberts CT. Seasonality of hypertensive disorders of pregnancy-a South Australian population study. Pregnancy Hypertens. 2018;12:118-23. https://doi.org/10.1016/j.preghy.2018.04.006 PMid:29674191 DOI: https://doi.org/10.1016/j.preghy.2018.04.006

Singh A, Mishra S, Aditya V, Srivastava R. Association of Vitamin D deficiency with occurrence of pre eclampsia among inpatients of tertiary care centre, Gorakhpur, Uttar Pradesh, India. Int J Reprod Contracept Obstetr Gynecol. 2016;5(5):1304-8. https://doi.org/10.18203/2320-1770.ijrcog20161280 DOI: https://doi.org/10.18203/2320-1770.ijrcog20161280

Anupama H, Sunanda K, Jyothirmayee R. Role of Vitamin-D supplementation in prevention of preeclampsia. IOSR J Dent Med Sci. 2016;15(9):51-5. DOI: https://doi.org/10.9790/0853-1509015155

Goel P, Garg G, Kaur J, Mehra R, Tandon R, Huria A. Association of Vitamin D deficiency during pregnancy with preeclampsia and eclampsia. Int J Reprod Contracept Obstetr Gynecol. 2016;5(9):3460-50. https://doi.org/10.18203/2320-1770.ijrcog20162982 DOI: https://doi.org/10.18203/2320-1770.ijrcog20162982

Umar N, Tauseef A, Shahzad F, Sabir S, Kanwal S, Akmal A, et al. Serum 25-hydroxy Vitamin D level in preeclamptic and normotensive pregnancies. J Coll Physicians Surg Pak. 2016;26(8):673-6. PMid:27539761

Yates N, Crew RC, Wyrwoll CS. Vitamin D deficiency and impaired placental function: Potential regulation by glucocorticoids? Reproduction. 2017;153:R163-71. https://doi.org/10.1530/rep-16-0647 PMid:28137896 DOI: https://doi.org/10.1530/REP-16-0647

Chan SY, Susarla R, Canovas D, Vasilopoulou E, Ohizua O, McCabe CJ, et al. Vitamin D promotes human extravillous trophoblast invasion in vitro. Placenta. 2015;36(4):403-9. https://doi.org/10.1016/j.placenta.2014.12.021 PMid:25596923 DOI: https://doi.org/10.1016/j.placenta.2014.12.021

Kim RH, Ryu BJ, Lee KM, Han JW, Lee SK. Vitamin D facilitates trophoblast invasion through induction of epithelial-mesenchymal transition. Am J Reprod Immunol. 2018;79(2):e12796. https://doi.org/10.1111/aji.12796 PMid:29205625 DOI: https://doi.org/10.1111/aji.12796

Smith TA, Kirkpatrick DR, Kovilam O, Agrawal DK. Immunomodulatory role of Vitamin D in the pathogenesis of preeclampsia. Expert Rev Clin Immunol. 2015;11(9):1055-63. https://doi.org/10.1586/1744666X.2015.1056780 PMid:26098965 DOI: https://doi.org/10.1586/1744666X.2015.1056780

Benian A, Madazli R, Aksu F, Uzun H, Aydin S. Plasma and placental levels of interleukin-10, transforming growth factor-beta1, and epithelial-cadherin in preeclampsia. Obstet Gynecol. 2002;100(2):327-31. https://doi.org/10.1016/s0029-7844(02)02077-x PMid:12151158 DOI: https://doi.org/10.1097/00006250-200208000-00021

Lai H, Liu H. Expression and meaning analysis of HIF-1α and HSP70inpreeclampticplacenta.BiomedRes.2018;29(6):1240-3. https://doi.org/10.4066/biomedicalresearch.29-17-3632 DOI: https://doi.org/10.4066/biomedicalresearch.29-17-3632

Akhilesh M, Mahalingam V, Nalliah S, Ali RM, Ganesalingam M, Haleagrahara N. Participation of hypoxia-inducible factor-1α in the pathogenesis of preeclampsia-related placental ischemia and its potential as a marker for preeclampsia. Biomark Genom Med. 2014;6(3):121-5. https://doi.org/10.1016/j.bgm.2014.04.002 DOI: https://doi.org/10.1016/j.bgm.2014.04.002

Matsubara K. Hypoxia in the pathogenesis of preeclampsia. Hypertens Res Pregnancy. 2017;5(2):46-51. https://doi.org/10.14390/jsshp.hrp2017-014 DOI: https://doi.org/10.14390/jsshp.HRP2017-014

Karumanchi SA, Rana S, Taylor RN. Angiogenesis and Preeclampsia. In: Chesley’s Hypertensive Disorders in Pregnancy. 4th ed. Netherlands: Elsevier; 2015. p. 113-25. DOI: https://doi.org/10.1016/B978-0-12-407866-6.00006-7

Khalil G, Hameed A. Preeclampsia: Pathophysiology and the maternal-fetal risk. J Hypertens Manag. 2017;3(1):024. https://doi.org/10.23937/2474-3690/1510024 DOI: https://doi.org/10.23937/2474-3690/1510024

Das CM, Shah N, Ghori A, Khursheed F, Zaheen Z. Prevalence and risk factors for cervical intraepithelial neoplasia in patients attending gynecological outpatient department of tertiary care hospital. J Liaquat Univ Med Health Sci. 2013;12(1):44-8.

Kumari N, Dash K, Singh R. Relationship between maternal age and preeclampsia. IOSR J Dent Med Sci. 2016;15(12):55-7. https://doi.org/10.9790/0853-1512085557

Sheen JJ, Huang Y, Andrikopoulou M, Wright JD, Goffman D, D’Alton ME, et al. Maternal age and preeclampsia outcomes during delivery hospitalizations. Am J Perinatol. 2020;37(1):44-52. https://doi.org/10.1055/s-0039-1694794 PMid:31430824 DOI: https://doi.org/10.1055/s-0039-1694794

Gold RA, Gold KR, Schilling MF, Modilevsky T. Effect of age, parity, and race on the incidence of pregnancy associated hypertension and eclampsia in the United States. Pregnancy Hypertens. 2014;4(1):46-53. https://doi.org/10.1016/j.preghy.2013.10.001 PMid:26104254 DOI: https://doi.org/10.1016/j.preghy.2013.10.001

Sulistyowati S. Early and late onset preeclamsia: What did really matter? J Gynecol Womens Health. 2017;5(4):555670. https://doi.org/10.19080/jgwh.ms.id.555670 DOI: https://doi.org/10.19080/JGWH.2017.05.555670

Chaiworapongsa T, Chaemsaithong P, Yeo L, Romero R. Pre- eclampsia part 1: Current understanding of its pathophysiology. Nat Rev Nephrol. 2014;10(8):466-80. https://doi.org/10.1038/nrneph.2014.102 PMid:25003615 DOI: https://doi.org/10.1038/nrneph.2014.102

ShiozakiA, Matsuda Y, Satoh S, Saito S. Comparison of risk factors for gestational hypertension and preeclampsia in Japanese singleton pregnancies. J Obstet Gynaecol Res. 2013;39(2):492-9. https://doi.org/10.1111/j.1447-0756.2012.01990.x PMid:23002807 DOI: https://doi.org/10.1111/j.1447-0756.2012.01990.x

Rich-Edwards JW, Klungsoyr K, Wilcox AJ, Skjaerven R. Duration of pregnancy, even at term, predicts long-term risk of coronary heart disease and stroke mortality in women: A population- based study. Am J Obstetr Gynecol. 2015;213(4):518.e1-8. https://doi.org/10.1016/j.ajog.2015.06.001 PMid:26070706 DOI: https://doi.org/10.1016/j.ajog.2015.06.001

Li X, Tan H, Huang X, Zhou S, Hu S, Wang X, et al. Similarities and differences between the risk factors for gestational hypertension and preeclampsia: A population based cohort study in South China. Pregnancy Hypertens. 2016;6(1):66-71. https://doi.org/10.1016/j.preghy.2015.11.004 PMid:26955775 DOI: https://doi.org/10.1016/j.preghy.2015.11.004

Yazdani M, Amirshahi E, Shakeri A, Amirshahi R, Malekmakan L. Prenatal and maternal outcomes in advanced maternal age, a comparative study. Womens Health Bull. 2015;2(2):1-5. https://doi.org/10.17795/whb-23092 DOI: https://doi.org/10.17795/whb-23092

Grundmann M, Haidar M, Placzko S, Niendorf R, Darashchonak N, Hubel CA, et al. Vitamin D improves the angiogenic properties of endothelial progenitor cells. Am J Physiol Cell Physiol. 2012;303(9):C954-62. https://doi.org/10.1152/ajpcell.00030.2012 PMid:22932684 DOI: https://doi.org/10.1152/ajpcell.00030.2012

Zhong Q, Kowluru RA. Regulation of matrix metalloproteinase-9 by epigenetic modifications and the development of diabetic retinopathy. Diabetes. 2013;62(7):2559-68. https://doi.org/10.2337/db12-1141 PMid:23423566 DOI: https://doi.org/10.2337/db12-1141

Park H, Wood MR, Malysheva OV, Jones S, Mehta S, Brannon PM, et al. Placental Vitamin D metabolism and its associations with circulating Vitamin D metabolites in pregnant women. Am J Clin Nutr. 2017;106(6):1439-48. https://doi.org/10.3945/ajcn.117.153429 PMid:29021285 DOI: https://doi.org/10.3945/ajcn.117.153429

Halhali A, Díaz L, Barrera D, Avila E, Larrea F. Placental calcitriol synthesis and IGF-I levels in normal and preeclamptic pregnancies. J Steroid Biochem Mol Biol. 2014;144 Pt A:44-9. https://doi.org/10.1016/j.jsbmb.2013.12.014 PMid:24373797 DOI: https://doi.org/10.1016/j.jsbmb.2013.12.014

Cornelius DC. Preeclampsia: From inflammation to immunoregulation. Clin Med Insights Blood Disord. 2018;11:1-6. https://doi.org/10.1177/1179545X17752325 PMid:29371787 DOI: https://doi.org/10.1177/1179545X17752325

Setiawati D. The role of inflammation in pathogenesis of preeclampsia: An investigation of interleukin-6, interleukin-10, and the ratio. Int J Med Rev Case Rep. 2020;4(10):13-7. https://doi. org/10.5455/ijmrcr.pathogenesis-preeclampsia-inflammation DOI: https://doi.org/10.5455/IJMRCR.pathogenesis-preeclampsia-inflammation

Fan DM, Wang Y, Liu XL, Zhang A, Xu Q. Polymorphisms in interleukin-6 and interleukin-10 may be associated with risk of preeclampsia. Genet Mol Res. 2017;16(1):1-8. https://doi.org/10.4238/gmr16018588 PMid:28252161 DOI: https://doi.org/10.4238/gmr16018588

Verma S, Pillay P, Naicker T, Moodley J, Mackraj I. Placental hypoxia inducible factor-1α & CHOP immuno-histochemical expression relative to maternal circulatory syncytiotrophoblast micro-vesicles in preeclamptic and normotensive pregnancies. Eur J Obstet Gynecol Reprod Biol. 2017;220:18-24. https://doi.org/10.1016/j.ejogrb.2017.11.004 PMid:29127866 DOI: https://doi.org/10.1016/j.ejogrb.2017.11.004

Fryer BH, Simon MC. Hypoxia, HIF and the placenta. Cell Cycle. 2006;5(5):495-8. https://doi.org/10.4161/cc.5.5.2497 PMid:16552177 DOI: https://doi.org/10.4161/cc.5.5.2497

Zhang Z, Huang C, Wang P, Gao J, Liu X, Li Y, et al. HIFα affects trophoblastic apoptosis involved in the onset of preeclampsia by regulating FOXO3a under hypoxic conditions. Mol Med Rep. 2020;21(6):2484-92. https://doi.org/10.3892/mmr.2020.11050 PMid:32323858 DOI: https://doi.org/10.3892/mmr.2020.11050

Redman CW, Sargent IL. Immunology of pre-eclampsia. Am J Reprod Immunol. 2010;63(6):534-43. https://doi.org/10.1111/j.1600-0897.2010.00831.x PMid:20331588 DOI: https://doi.org/10.1111/j.1600-0897.2010.00831.x

Noyola-Martínez N, Díaz L, Avila E, Halhali A, Larrea F, Barrera D. Calcitriol downregulates TNF-α and IL-6 expression in cultured placental cells from preeclamptic women. Cytokine. 2013;61(1):245-50. https://doi.org/10.1016/j.cyto.2012.10.001 PMid:23103122 DOI: https://doi.org/10.1016/j.cyto.2012.10.001

Washington K, Ghosh S, Reeves IV. A review: Molecular concepts and common pathways involving Vitamin D in the pathophysiology of preeclampsia. Open J Obstetr Gynecol. 2018;8(3):198-229. https://doi.org/10.4236/ojog.2018.83023 DOI: https://doi.org/10.4236/ojog.2018.83023

Suo Z, Liu Y, Li Y, Xu C, Liu Y, Gao M, et al. Calcitriol inhibits COX-1 and COX-2 expressions of renal vasculature in hypertension: Reactive oxygen species involved? Clin Exp Hypertens. 2021;43(1):91-100. https://doi.org/10.1080/10641963.2020.1817473 PMid:32909857 DOI: https://doi.org/10.1080/10641963.2020.1817473

Kim DH, Meza CA, Clarke H, Kim JS, Hickner RC. Vitamin D and endothelial function. Nutrients. 2020;12(2):575. https://doi.org/10.3390/nu12020575 PMid:32098418 DOI: https://doi.org/10.3390/nu12020575