Molecular evidence of a (pro)renin/ (pro)renin receptor system in human intrauterine tissues in pregnancy and its association with PGHS-2

Abstract

Prorenin stimulates decidual prostaglandin (PG) production in vitro, the (pro)renin receptor ((P)RR) may mediate this action. The role of prorenin in amnion PG synthesis has not been examined, despite this being the key site of PG synthesis. To determine if (P)RR, prorenin and PGHS-2 are co-localized in gestational tissues and if expression is altered by labour, term amnion, chorion, decidua and placenta were collected during elective caesarean section or after spontaneous labour. Prorenin, (P)RR and PGHS-2 mRNA abundance was determined by real-time RT-PCR. (P)RR protein was examined by immunohistochemistry. The effect of recombinant human (rh) prorenin on PGHS-2 mRNA abundance in amnion explants was determined. Prorenin and (P)RR mRNA were highest in decidua and placenta, respectively. Decidual prorenin, (P)RR and placental (P)RR mRNA abundance decreased with labour. (P)RR protein was present in all gestational tissues. After labour, decidual prorenin was positively correlated with amnion PGHS-2 mRNA and rh-prorenin significantly increased PGHS-2 mRNA abundance in amnion explants. We conclude that the decidua is the principal source of prorenin and is downregulated with labour. All gestational tissues are targets for prorenin. Decidual prorenin may be involved in the labour-associated increase in amnion PGHS-2 abundance via the (P)RR.

Keywords

Labour pregnancy prorenin (pro)renin receptor renin—angiotensin system

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References

Morris BJ and Lumbers ER The activation of renin in human amniotic fluid by proteolytic enzymes. Biochim Biophys Acta 1972; 289: 385-391.

Lumbers ER Activation of renin in human amniotic fluid by low pH. Enzymologia 1971; 40: 29-336.

Nguyen G. , Delarue F. , Burcklé C. , Bouzhir L. , Giller T. and Sraer JD Pivotal role of the renin/prorenin receptor in angiotensin II production and cellular responses to renin. J Clin Invest, 2002; 109: 417-1427.

Batenburg WW , Krop M. , Garrelds IM , de Vries R. , de Bruin RJ , Burcklé C. , et al. Prorenin is the endogenous agonist of the (pro)renin receptor. Binding kinetics of renin and prorenin in rat vascular smooth muscle cells overexpressing the human (pro)renin receptor. J Hypertens 2007; 25: 441-2453.

Saris JJ , ‘tHoen PA, Garrelds IM , Dekkers DH , den Dunnen JT , Lamers JM , et al. Prorenin Induces Intracellular Signaling in Cardiomyocytes Independently of Angiotensin II. Hypertension 2006; 48: 64-571.

Skinner SL , Lumbers ER and Symonds EM Renin concentration in human fetal and maternal tissues. Am J Obstet Gynecol 1968; 101: 529-533.

Zakar T. and Hertelendy F. Progesterone withdrawal: key to parturition. Am J Obstet Gynecol 2007; 196 : 289-296.

Mitchell MD , Edwein SS , Pollard JK and Trautman MS Renin stimulates decidual prostaglandin production via a novel mechanism that is independent of angiotensin II formation. Placenta 1996; 17: 299-305.

Lundin-Schiller S. and Mitchell MD Renin increases human amnion cell prostaglandin E2 biosynthesis. J Clin Endocrinol Metab 1991 ; 73: 436-440.

10.

Zakar T. and Hertelendy F. Regulation of prostaglandin synthesis in the human uterus. J Matern Fetal Med 2001; 10: 223-235.

11.

Powell WA , Mitchell BF and Challis JR Effects of steroids on progesterone output by explants of human chorion. Gynecol Obstet Invest 1986; 22: 64-72.

12.

Johnson RF , Mitchell CM , Giles WB , Walters WA and Zakar T. The control of prostaglandin endoperoxide H-Synthase-2 expression in the human chorion laeve at term. J Soc Gynecol Investig 2003; 10: 222-230.

13.

Gilsbach R. , Kouta M. , Bonisch H. and Bruss M. Comparison of in vitro and in vivo reference genes for internal standardization of real-time PCR data. Biotechniques 2006; 40: 173-177.

14.

Johnson RF , Mitchell CM , Giles WB , Walters WA and Zakar T. The in vivo control of prostaglandin h synthase-2 messenger ribonucleic acid expression in the human amnion at parturition. J Clin Endocrinol Metab 2002; 87: 2816-2823.

15.

Livak KJ and Schmittgen TD Analysis of relative gene expression data using real-time quantitative PCR and the 2-[Delta][Delta]CT method. Methods 2001; 25: 402-408.

16.

Dorer FE , Lentz KE , Kahn JR , Levine M. and Skeggs LT A comparison of the substrate specificities of cathepsin D and pseudorenin . J Biol Chem 1978; 253: 3140-3142.

17.

Hanssens M. , Pijnenborg R. , Keirse MJ , Vercruysse L. , Vernbist L. and Van Assche FA Renin-like immunoreactivity in uterus and placenta from normotensive and hypertensive pregnancies. Eur J Obstet Gynecol Reprod Biol 1998; 81: 177-184.

18.

Li C. , Ansari R. , Yu Z. and Shah D. Definitive molecular evidence of renin-angiotensin system in human uterine decidual cells. Hypertension 2000; 36: 159-164.

19.

Shaw KJ , Do YS , Kjos S. , Anderson PW , Shinagawa T. , Dubeau L. , et al. Human decidua is a major source of renin. J Clin Invest 1989; 83: 2085-2092.

20.

Symonds EM , Stanley MA and Skinner SL Production of renin by in vitro cultures of human chorion and uterine muscle . Nature 1968; 217: 1152-1153.

21.

Krebs C. , Hamming I. , Sadaghiani S. , Steinmetz OM , Meyer-Schwesinger C. , Fehr S. , et al. Antihypertensive therapy upregulates renin and (pro)renin receptor in the clipped kidney of Goldblatt hypertensive rats. Kidney Int 2007; 72: 725-730.

22.

Itskovitz J. , Rubattu S. , Levron J. and Sealey JE Highest concentrations of prorenin and human chorionic gonadotropin in gestational sacs during early human pregnancy. J Clin Endocrinol Metab 1992; 75: 906-910.

23.

Kaneshiro Y. , Ichihara A. , Takemitsu T. , Sakoda M. , Suzuki F. , Nakagawa T. , et al. Increased expression of cyclooxygenase-2 in the renal cortex of human prorenin receptor gene-transgenic rats. Kidney Int 2006; 70: 641-646.

24.

Zakar T. , Mijovic JE , Eyster KM , Bhardwaj D. and Olson DM Regulation of prostaglandin H2 synthase-2 expression in primary human amnion cells by tyrosine kinase dependent mechanisms. Biochimica et Biophysica Acta 1998; 1391: 37-51.

25.

Lumbers ER , et al. The identification and role of the intrauterine (pro)renin/(pro)renin receptor angiotensin system in prostaglandin synthesis in pregnancy. Reprod Sci 2009; 16(Suppl.): A168.