Effect of L- Arginin on Placental Hipoxia Inducible Factor -1-Alpha (HIF-1-A) Expression at Preeclampsia Mice Models

Nutria Widya Purna Anggraini, Sri Sulistyowati, Besari Adi Pramono, Herman Kristanto


Background: Placental hypoxia is one of the theories that cause preeclampsia. In placental hypoxia of preeclampsia, there is an increase of Hipoxia Inducible Factor 1 Alpha (HIF-1-A) expression as a response to hypoxia. L-Arginine administration through the L-Arginine-Nitric Oxide pathway is expected to improve placental hypoxia. This study aimed to examine the effect of L- Arginin on placental HIF-1-A expression at preeclampsia mice models.
Subjects and Method: Experimental study with parallel group post-test only design. The study was carried out at the Veterinary Medicine Faculty of Airlangga University. Thirty six preeclampsia mice models were made with intravenous injection 10ng anti-Qa-2 on day 1-4 of pregnancy. They were divided into 2 groups: (1)18 mice without treatment (control) and (2) 18 mice were given L-Arginin 200 mg/kgBW/day on day 7-15 of pregnancy. They were terminated on day 16 then immunohistochemistry examination of HIF-1-A expression was done on the placental samples. The dependent variable was placental Hipoxia Inducible Factor-1-Alpha (HIF-1-A) expression. The independent variables were L-Arginin administration. HIF-1-A expression was measured by H-Score method. The data were analyzed by t-test.
Results: The mean of placental HIF-1-A expressions of treatment group was lower (Mean= 7.98; SD=9.35) than control group (Mean=41.95; SD= 32.20), and it was statistically significant (p <0.001).
Conclusion: L-Arginin reduces the Placental Hypoxia Inducible Factor Alpha (HIF-1-A) expression on preeclampsia mice model.
Keywords: L-Arginine, HIF-1-A, Preeclampsia
Correspondence: Nutria Widya Purna Anggraini. Department of Obstetrics and Gynecology, Faculty of Medicine Universitas Sebelas Maret/ Dr. Moewardi General Hospital Surakarta. Jl Kolonel Sutarto 132, Surakarta, Central Java, Indonesia. Email: Mobile: 08122651819.

Indonesian Journal of Medicine (2020), 05(03): 191-199


Full Text:



Al-Bayati MA, Ahmad MA, Khamas W (2014). The potential effect of l-arginine mice placenta. Adv Pharmacoepidemiol Drug Saf, 3(2): 1-9.

Asif A and Wenda R (2015). Unraveling the theories of pre-eclampsia: are the protective pathways the new paradigm?. Br J Pharmacol, 172(6): 1574–86.

Burke S and Karumanchi (2013). A Spiral artery remodeling in preeclampsia revisited. Hypertension,(62) :1013-4.

Cheryl LML (2015). Female reproductive tract. In : A practical Guide Hystology of the Mouse. 6th ed. Milton (Australia): John Wiley 7 Sons, p.88-97.

Facchinetti F, Farulla A. (2017)Dietary suplements and drugs for preeclampsia prophylaxis. Journal of Women’s Cardiovascular Health. (7): 59

Gao K, Jiang Z, Lin Y, Zheng C, Zhou G, Chen F, Wu G (2011). Dietary l-arginine supplementation enhances placental growth and reproductive performance in sows. Amino Acids, 42(6), 2207–2214.

Grafka A, Lopucki M, Karwasik-Kajszczarek K, Stasiak-Kosarzycka M, Miturski A, Dzida G (2016). Study of the role l-arginine in the diagnosis of pregnancy induced hypertension Arterial Hypertens, 20 (3): 113-8.

Himpunan Kedokteran Fetomaternal (2017). Pedoman nasional pelayanan kedokteran tata laksana komplikasi kehamilan. Jakarta: Kementerian Kesehatan Republik Indonesia,hal. 23-48.

Kooffreh ME, Ekott M, Ekpoudom DO (2014). The prevalence of preeclampsia among pregnant women in the university of calabar teaching hospital, calabar. Saudi J Health Sci, (3):133-6.

Korkes HA, De Oliveira L, Sass N, Salahuddin S, Karumanchi SA, Rajakumar A (2017). Relationship between hypoxia and downstream pathogenic pathways in preeclampsia. Hypertension in Pregnancy, 36(2), 145–150.

Ibrahim NA, Khaled DM (2014). Histological and immunohistochemical study on human placental tissue in normal pregnancy and preeclampsia. Nat Cell Biol, 2(6): 72-80.

Lassala A, Bazer FW, Cudd TA, Datta S, Keisler DH, Satterfield MC, Spencer TE, et al (2011). Parenteral adminis-tration of l-arginine enhances fetal survival and growth in sheep carrying multiple fetuses. J Nutr, 141(5): 849–55.

Lyall F, Bellfort MA (2007). Preeclampsia: etiology and clinical practice. New York: Cambridge University Press.

Ohta H, Kaga M, Li H, Sakai H, Okamura K, Yaegashi N (2017). Potential new non-invasive therapy using artificial oxygen carriers for preeclampsia. J Funct Biomater. 8(3): 32. https://doiorg/10.3390/jfb8030032.

Patel J, Landers K, Mortimer RH, Ricard K (2010). Regulation of hypoxia inducible factors (HIF) in hypoxia and normoxia during placental development. Placenta. 31(11): 951-7.

Provincial Health Office of Central Java (2015). Profil kesehatan provinsi jawa tengah tahun 2015[internet]. Available from: https://www.

Robb KP, Cotechini T, Allaire C, Sperou A, Graham CH (2017). Inflammation-induced fetal growth restriction in rats is associated with increased placental HIF-1α accumulation. Plos One, 12-(4), e0175805.

Sánchez-Aranguren LC, Prada CE, Riaño-Medina CE, Lopez M (2014). Endo-thelial disfunction and preeclampsia: role of oxidative stress. Front Physiol. (5): 372.

Tal R (2012). The role of hypoxia and hypoxia inducible factor 1 alpha in preeclampsia pathogenesis. Biol Reprod, 87(6): 1-8.

Roberts JM, Hubel CA (2009). The two stage model of preeclampsia: variations on the theme. Placenta. (23): 32–7.

Roberts MD, Phyllis A (2013). Task force on hypertension in pregnancy. In: Hypertension in pregnancy. ACOG. (2): 1-11. Available from:

Semenza G (2011). Hypoxia inducible factor 1: ;Regulator of mitochondrial metabolism and mediator of ischemic pre-conditioning. Biochim Biophys Acta. 13(7): 1263-8.

Soetrisno S, Sulistyowati S, Wibowo AS (2017). L-arginine improves uterine spiral arterial wall thickness in mouse model of preeclampsia. Univ Med. 36 (2):131-7.

Supranto J (2010). Teknik sampling untuk survey dan eksperimen. Jakarta: PT. Rineka Cipta.

Verma S, Pillay P, Naicker T, Moodley J, Mackraj I (2018). 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. 220: 18-24.

Wall TD, Grivell RM, Dekker GA, Hague W, Dodd JM (2014). The role of L-Arginin in the prevention and treatment of pre-eclampsia: a systematic review of randomised trials. J Hum Hypertens, 28(4): 230–5.

Wantania J, Bakri S, Pandelaki K, Chalid M (2013). Altered level of soluble fms like tyrosine kinase 1 (sFlt1) and hypoxia inducible factor 1alpha (HIF-1Alpha) in normotensive pregnancy and preeclampsia. Indones Biomed J. 5(2): 121-8.

Woods AK, Hoffmann DS, Weydert CJ, Butler SD, Zhou Y, Sharma RV, Davisson RL (2011). Adenoviral delivery of vegf 121 early in pregnancy prevents spontaneous development of preeclampsia in bph/5 mice. Hypertension. 57(1): 94-102.


  • There are currently no refbacks.