The expression of angiogenic protein Cyr61 significantly increases in the urine of early-onset preeclampsia patients

Yıl 2021, Cilt: 11 Sayı: 5, 605 - 609, 17.09.2021

Mustafa Behram Süleyman Cemil Oğlak

https://doi.org/10.16899/jcm.945345

Cited By: 6

Öz

Aim: This study sought to compare the expression of the Cysteine-rich 61 (Cyr61) protein in the urine of early-onset preeclampsia (PE) patients with that of the urine of normotensive healthy pregnant women.
Material and method: A total of 80 patients who gave birth from June 2019 to December 2019 were enrolled in this prospective study. The study group comprised 40 pregnant women at 20-34 weeks of gestation who presented with early-onset PE. Gestational age- and body mass index-matched, 40 healthy normotensive pregnant women without proteinuria were included in the control group. We recorded demographic characteristics and urine Cyr61 concentrations of the participants.
Results: The urine Cyr61 protein levels were significantly higher in the early-onset PE group (922.6±1263.1 pg/mL) than those of the control group (499.2±270.2 pg/mL, p<0.001). As a result of the ROC analysis, the area under the curve (aHR=0.690, 95% CI=0.556-0.813) was found to be significant (p=0.003). So, it was seen that Cyr61 could be used for the diagnosis of early-onset PE. The values 981.52 pg/mL and above, corresponding to 67.5% of sensitivity and 72.5% of specificity points, can be used as a cut-off which is calculated by the Youden index, can be used to diagnose early-onset PE.
Conclusion: This study found an increased Cyr61 protein level in the urine of the early-onset PE patients compared with the urine of healthy pregnancies. The increased presence of Cyr61 protein in the urine could serve as a predictive tool for the early diagnosis of early-onset PE and renal ischemia.

Anahtar Kelimeler

Cysteine-rich protein 61, early-onset preeclampsia, renal ischemia

Anjiyojenik protein Cyr61’in ekspresyonu, erken başlangıçlı preeklampsi hastalarının idrarında önemli ölçüde artar

Öz

Amaç: Bu çalışma, erken başlangıçlı preeklampsi (PE) hastalarının idrarındaki Sistein açısından zengin 61 (Cyr61) proteinin ekspresyonunu normotansif sağlıklı hamile kadınların idrarıyla karşılaştırmayı amaçladı.
Gereç ve Yöntem: Bu prospektif çalışmaya Haziran 2019 ile Aralık 2019 tarihleri arasında doğum yapan toplam 80 hasta dahil edildi. Çalışma grubu, erken başlangıçlı PE ile başvuran 20-34. gebelik haftalarındaki 40 gebe kadından oluşturuldu. Kontrol grubuna, gebelik yaşı ve vücut kitle indeksi uyumlu, proteinürisi olmayan 40 sağlıklı normotansif gebe alındı. Katılımcıların demografik özelliklerini ve idrar Cyr61 konsantrasyonlarını kaydettik.
Bulgular: İdrar Cyr61 protein seviyeleri erken başlangıçlı PE grubunda (922.6±1263.1 pg/mL) kontrol grubuna (499.2±270.2 pg/mL, p<0.001) anlamlı ölçüde daha yüksekti. ROC analizi sonucunda, eğri altındaki alan (aHR=0.690, 95% CI=0.556-0.813) anlamlı bulundu (p=0.003). Böylece, Cyr61’in erken başlangıçlı PE tanısında kullanılabileceği görüldü. Youden indeksi ile hesaplanan, %67,5 sensitivite ve %72,5 özgüllük noktalarına karşılık gelen 981.52 pg/mL eşik değeri erken başlangıçlı PE’yi teşhis etmek için kullanılabilir.
Sonuç: Bu çalışma, erken başlangıçlı PE hastalarının idrarında sağlıklı gebelerin idrarına kıyasla yüksek Cyr61 protein düzeyi bulmuştur. İdrarda artan Cyr61 protein düzeyinin varlığı, erken başlangıçlı PE ve renal iskeminin erken teşhisi için öngörücü bir belirteç olarak kullanılabilir.

Anahtar Kelimeler

Sistein açısından zengin protein 61, erken başlangıçlı preeklampsi, renal iskemi

Kaynakça

• 1. Behram M, Oğlak SC, Doğan Y. Evaluation of BRD4 levels in patients with early-onset preeclampsia. J Gynecol Obstet Hum Reprod. 2021;50(2):101963.
• 2. Oğlak SC, Tunç Ş, Obut M, Şeker E, Behram M, Tahaoğlu AE. Maternal near-miss patients and maternal mortality cases in a Turkish tertiary referral hospital. Ginekol Pol. 2021;92(4):300-305.
• 3. Mannaerts D, Heyvaert S, De Cordt C, Macken C, Loos C, Jacquemyn Y. Are neutrophil/lymphocyte ratio (NLR), platelet/lymphocyte ratio (PLR), and/or mean platelet volume (MPV) clinically useful as predictive parameters for preeclampsia?. J Matern Fetal Neonatal Med. 2019;32(9):1412-1419.
• 4. Oğlak SC, Bademkıran MH, Obut M. Predictor variables in the success of slow-release dinoprostone used for cervical ripening in intrauterine growth restriction pregnancies. J Gynecol Obstet Hum Reprod. 2020;49(6):101739.
• 5. Mol BWJ, Roberts CT, Thangaratinam S, Magee LA, de Groot CJM, Hofmeyr GJ. Pre-eclampsia. Lancet. 2016;387(10022):999-1011.
• 6. Behram M, Oğlak SC, Dağ İ. Circulating levels of Elabela in pregnant women complicated with intrauterine growth restriction. J Gynecol Obstet Hum Reprod. 2021;50(8):102127.
• 7. Fisher SJ. Why is placentation abnormal in preeclampsia?. Am J Obstet Gynecol. 2015;213(4 Suppl):S115-S122.
• 8. Knöfler M, Haider S, Saleh L, Pollheimer J, Gamage TKJB, James J. Human placenta and trophoblast development: key molecular mechanisms and model systems. Cell Mol Life Sci. 2019;76(18):3479-3496.
• 9. Kwak YT, Muralimanoharan S, Gogate AA, Mendelson CR. Human Trophoblast Differentiation Is Associated With Profound Gene Regulatory and Epigenetic Changes. Endocrinology. 2019;160(9):2189-2203.
• 10. Oğlak SC, Aydın MF. Are neutrophil to lymphocyte ratio and platelet to lymphocyte ratio clinically useful for the prediction of early pregnancy loss? Ginekol Pol. 2020;91(9):524-527.
• 11. Zhang Y, Cao L, Jia J, Ye L, Wang Y, Zhou B, et al. CircHIPK3 is decreased in preeclampsia and affects migration, invasion, proliferation, and tube formation of human trophoblast cells. Placenta. 2019;85:1-8.
• 12. Obut M, Oğlak SC. Expression of CD44 and IL-10 in normotensive and preeclamptic placental tissue. Ginekol Pol. 2020;91(6):334-341.
• 13. Wolf N, Yang W, Dunk CE, Gashaw I, Lye SJ, Ring T, et al. Regulation of the matricellular proteins CYR61 (CCN1) and NOV (CCN3) by hypoxia-inducible factor-1{alpha} and transforming-growth factor-{beta}3 in the human trophoblast. Endocrinology. 2010;151(6):2835-2845.
• 14. Zhang Y, Diao Z, Su L, Sun H, Li R, Cui H, et al. MicroRNA-155 contributes to preeclampsia by down-regulating CYR61. Am J Obstet Gynecol. 2010;202(5):466.e1-466.e4667.
• 15. Gellhaus A, Schmidt M, Dunk C, Lye SJ, Kimmig R, Winterhager E. Decreased expression of the angiogenic regulators CYR61 (CCN1) and NOV (CCN3) in human placenta is associated with pre-eclampsia. Mol Hum Reprod. 2006;12(6):389-399.
• 16. Gellhaus A, Schmidt M, Dunk C, Lye SJ, Winterhager E. The circulating proangiogenic factors CYR61 (CCN1) and NOV (CCN3) are significantly decreased in placentae and sera of preeclamptic patients. Reprod Sci. 2007;14(8 Suppl):46-52.
• 17. Chen X, Liu Y, Xu X, Chen H. Decreased Cyr61 under hypoxia induces extravillous trophoblasts apoptosis and preeclampsia. J Huazhong Univ Sci Technolog Med Sci. 2011;31(2):235-240.
• 18. Di Leo V, Capaccio F, Gesualdo L. Preeclampsia and Glomerulonephritis: A Bidirectional Association. Curr Hypertens Rep. 2020;22(5):36.
• 19. Choi SY, Kim KH, Lee M, Yeo MK, Kim J, Suh KS. Complement Component C4d Deposition in the Placenta of Preeclampsia Patients and Renal Glomeruli in 1 Postpartum Renal Biopsy. Appl Immunohistochem Mol Morphol. 2020;28(2):139-145.
• 20. Moghaddas Sani H, Zununi Vahed S, Ardalan M. Preeclampsia: A close look at renal dysfunction. Biomed Pharmacother. 2019;109:408-416.
• 21. Zhang X, Ding L, Diao Z, Yan G, Sun H, Hu Y. CYR61 modulates the vascular endothelial growth factor C expression of decidual NK cells via PI3K/AKT pathway. Am J Reprod Immunol. 2012;67(3):216-223.
• 22. Li C, Zhao L, Wang Y, Che L, Luan H, Luo C, et al. Cysteine-rich protein 61, a specific ultra-early biomarker in kidney ischemia/reperfusion injury. Nephrology (Carlton). 2019;24(8):798-805.
• 23. ACOG Practice Bulletin No. 202: Gestational Hypertension and Preeclampsia. Obstet Gynecol. 2019;133(1):e1-e25.
• 24. Phipps EA, Thadhani R, Benzing T, Karumanchi SA. Pre-eclampsia: pathogenesis, novel diagnostics and therapies. Nat Rev Nephrol. 2019;15(5):275-289.
• 25. Szczepanski J, Griffin A, Novotny S, Wallace K. Acute Kidney Injury in Pregnancies Complicated With Preeclampsia or HELLP Syndrome. Front Med (Lausanne). 2020;7:22.
• 26. Wiles K, Chappell L, Clark K, Elman L, Hall M, Lightstone L, et al. Clinical practice guideline on pregnancy and renal disease. BMC Nephrol. 2019;20(1):401.
• 27. Han L, Yang Z, Li K, Zou J, Li H, Han J, et al. Antepartum or immediate postpartum renal biopsies in preeclampsia/eclampsia of pregnancy: new morphologic and clinical findings. Int J Clin Exp Pathol. 2014;7(8):5129-5143.
• 28. Moghaddas Sani H, Zununi Vahed S, Ardalan M. Preeclampsia: A close look at renal dysfunction. Biomed Pharmacother. 2019;109:408-416.
• 29. Wang Y, Zhao S, Gu Y, Lewis DF. Loss of slit protein nephrin is associated with reduced antioxidant superoxide dismutase expression in podocytes shed from women with preeclampsia. Physiol Rep. 2018;6(13):e13785.
• 30. Wang Y, Gu Y, Loyd S, Jia X, Groome LJ. Increased urinary levels of podocyte glycoproteins, matrix metallopeptidases, inflammatory cytokines, and kidney injury biomarkers in women with preeclampsia. Am J Physiol Renal Physiol. 2015;309(12):F1009-F1017.
• 31. Muramatsu Y, Tsujie M, Kohda Y, Pham B, Perantoni AO, Zhao H, et al. Early detection of cysteine rich protein 61 (CYR61, CCN1) in urine following renal ischemic reperfusion injury. Kidney Int. 2002;62(5):1601-1610.
• 32. Fakhouri F, Vercel C, Frémeaux-Bacchi V. Obstetric nephrology: AKI and thrombotic microangiopathies in pregnancy. Clin J Am Soc Nephrol. 2012;7(12):2100-2106.
• 33. Lai CF, Lin SL, Chiang WC, Chen YM, Wu VC, Young GH, et al. Blockade of cysteine-rich protein 61 attenuates renal inflammation and fibrosis after ischemic kidney injury. Am J Physiol Renal Physiol. 2014;307(5):F581-F592.
• 34. Liu H, Zhang J, Liu X, Li C, Ma R, Xu Y. Effect and mechanism of cysteine⁃ rich protein 61 on transforming growth factor-β1-activated renal fibroblasts. Chinese Journal of Nephrology. 2017;9:704-10.