The G Protein-Coupled Estrogen Receptor (GPER-1): A Novel Regulator in the Kidney

Zijun Liu, Na Liu and Shibin Cheng*

Corresponding Author

Shibin Cheng, MD, PhD, Assistant Professor, Department of Pediatrics, Women & Infants Hospital, Warren Alpert Medical School of Brown University, Providence, RI, USA, E-mail: shibin_cheng@brown.edu

Co-Corresponding author

Zijun Liu, MD, PhD, Physician-in-Chief , Department of General Surgery, Nanjing First Hospital, Nanjing Medical University, Nanjing, China, E-mail: liuzijundoctor@sina.com

Affiliation

Zijun Liu1*, Na Liu2 and Shibin Cheng3*

1 Department of General Surgery, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
2 Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
3 Department of Pediatrics, Women & Infants Hospital, Warren Alpert Medical School of Brown University, Providence, RI, USA

Corresponding Author

Shibin Cheng, MD, PhD, Assistant Professor, Department of Pediatrics, Women & Infants Hospital, Warren Alpert Medical School of Brown University, Providence, RI, USA, E-mail: shibin_cheng@brown.edu

Co-Corresponding author

Zijun Liu, MD, PhD, Physician-in-Chief , Department of General Surgery, Nanjing First Hospital, Nanjing Medical University, Nanjing, China, E-mail: liuzijundoctor@sina.com

Article History

Received: April 16th, 2015, Accepted: April 16th, 2015, Published: April 17th, 2015

Cite this Article

Liu Z, Liu N, Cheng S. The G proteincoupled estrogen receptor (GPER1): a novel regulator in the kidney. Nephrol Open J. 2015; 1(1): e4-e6. doi: 10.17140/NPOJ-1-e002

Copyright

Ā© 2015 Cheng S. This is an open access article distributed under the Creative Commons Attribution 4.0 International License (CC BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Doi

10.17140/NPOJ-1-e002

Gender has a crucial influence on incidence and prognosis of chronic and acute kidney diseases since women generally have a lower morbidity and mortality compared to men.1,2 Several studies have reported the capability of estrogen to promote homeostatic and protective effects in the kidney via a pregenomic mechanism that is mediated by G protein-coupled receptor 30 (GPR30), but not by classic Estrogen Receptors (ER), ERĪ± or ERĪ².2 GPR30 was first cloned as an orphan receptor from a Burkittā€™s lymphoma cell line3 and then confirmed in other cell lines.4 Prior studies have demonstrated that GPR30 is a specific, high affinity, Gs -coupled estrogen membrane receptor activated by naturally occurring and synthetic estrogens and antiestrogens including estradiol-17Ī², G1, tamoxifen, ICI182,780, Genestein and Bisphenol A, but not by cortisol, progesterone or testosterone in both mammals and fish.5-15 Thus, GPR30 was designated G protein-coupled estrogen receptor-1 (GPER-1) by the International Union of Pharmacology in 2007.16

GPER-1 is highly expressed in kidney tissues albeit with differences regarding its subcellular distribution, which may in part be due to differences in methodological approaches in measuring its expression and activity.17-21 Recently, Filardo and coworkers evaluated the topographic mapping of GPER-1 expression in renal tubules using dual immunostaining of the receptors and specific markers for distinct tubules in tissue section.22 The results revealed that GPER-1 immunoreactivity is mainly localized in the distal convoluted tubules and the loop of Henle, and to a lower level in the proximal convoluted tubules.22 Interestingly, the subcellular distribution pattern of GPER-1 in these tubules is distinct: GPER-1 in the distal convoluted tubules and the loop of Henle mainly resides in the cytoplasm with less GPER-1 in the basolateral plasma membrane, whereas GPER-1 in the proximal convoluted tubules is primarily located in the basolateral membrane.22 Similar pattern for GPER-1 expression has been observed in male rat renal epithelia.19 Intriguingly, subcellular distribution of GPER-1 is modulated during the estrus cycle. During the secretory phases of the estrus cycle, GPER-1 is upregulated on cortical epithelia and localized to the basolateral surface during proestrus and redistributed intracellularly during estrus. GPER-1 is down-modulated during luteal phases of the estrus cycle with significantly less receptors on the surface of renal epithelia.22 Lindsey and colleagues reported that GPER-1 imunoreactivity is predominantly localized to the apical surface of the proximal tubule and minimally to the glomerulus but not to the distal tubules in female hypertensive rat.20 Differences in the subcellular distribution pattern and topographic localization of GPER-1 in distinct renal tubules may suggest that GPER-1 plays differential roles in mediating fluid and electrolyte homeostasis, and that pathological conditions such as hypertension may influence subcellular translocation of GPER-1 in renal epithelia.

Accumulating evidence has shown multiple roles for GPER-1 in the kidney in the context of physiological and pathological conditions. The specific GPER-1 agonist, G1,15 estradiol-17Ī² (E2), and ICI 182,780 (the ER antagonist and GPER-1 agonist)12 have been reported to increase acute Ca2+ concentration and H+ -ATPase activity intracellular calcium signals in microdissected renal tubule segments and isolated intercalated cells but not in similar explants and cell cultures isolated from GPER-1-deleted mice, suggesting a role for GPER-1 in regulating Na+ and Ca2+ reabsorption in renal tubules and subsequently affecting fluid retention.21 Prior studies revealed that G1 and estradiol-17Ī² induce vasodilation in female mouse, pig and rat and vasoconstriction in male rat.23 A recent study demonstrated that GPER-1 exerts beneficial effects on preventing excessive mesangial matrix production and modulates mesangial cell migration.2 Chappell and co-workers have shown that GPER-1 colocalizes with megalin in renal proximal tubules and that G1 ameliorates salt-induced renal injury in female mRen2. Lewis mice independently of changes in systolic blood pressure.20 Estrogen has been shown to ameliorateischemic glomerular endothelial hyperpermeability via a GPER-1- mediated mechanism.1

Collectively, while more work is required to elucidate the physiological significance of GPER-1 modulation in the kidney, current findings strongly suggest that GPER-1 in the kidney facilitates selective reabsorption of water and electrolytes, mediates renal vascular activities and mesangial cell behavior and reduces proteinuria and oxidative stress.

 

1. Hutchens MP, Fujiyoshi T, Komers R, Herson PS, Anderson S. Estrogen protects renal endothelial barrier function from ischemia-reperfusion in vitro and in vivo. Am. J. Physiol. Renal. Physiol. 2012; 303: F377-F385. doi: 10.1152/ajprenal.00354.2011

2. Li YC, Ding XS, Li HM, Zhang Y, Bao J. Role of G proteincoupled estrogen receptor 1 in modulating transforming growth factor-Ī² stimulated mesangial cell extracellular matrix synthesis and migration. Mol Cell Endocrinol. 2014; 391(1-2): 50-59. doi: 10.1016/j.mce.2014.04.014

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5. Filardo EJ, Thomas P. GPR30: a seven-transmembranespanning estrogenreceptor that triggers EGF release. Trends Endocrinol. Metab. 2005; 16: 362-367. doi: 10.1016/j. tem.2005.08.005

6. Filardo EJ, Thomas P. Mini review: G protein-coupled estrogen receptor-1, GPER-1: its mechanism of action and role in female reproductive cancer, renal and vascular physiology. Endocrinology. 2012; 153: 2953-2962. doi: 10.1210/en.2012-1061

7. Filardo EJ, Quinn JA, Bland KI, Frackelton Jr, AR. Estrogeninduced activation of Erk-1 and Erk-2 requires the G proteincoupled receptor homolog, GPR30, and occurs via trans-activation of the epidermal growth factor receptor through release of HB-EGF. Mol. Endocrinol. 2000; 14: 1649-1660.

8. Filardo EJ, Quinn JA, Frackelton Jr AR, Bland KI. Estrogen action via the G protein-coupled receptor, GPR30: stimulation of adenylyl cyclase and cAMP mediated attenuation of the epidermal growth factor receptor-to-MAPK signaling axis. Mol. Endocrinol. 2002; 16: 70-84.

9. Filardo EJ, GraeberCT, Quinn JA, et al. Distribution of GPR30, a seven membrane-spanning estrogen receptor, in primary breast cancer and its association with clinicopathologic determinants of tumor progression. Clin. Cancer Res. 2006; 12: 6359-6366. doi: 10.1158/1078-0432.CCR-06-0860

10. Filardo E, Quinn J, Pang Y, et al. Activation of the novel estrogen receptor G protein-coupled receptor 30 GPR30.at the plasma membrane. Endocrinology. 2007; 148: 3236-3245. doi: 10.1210/en.2006-1605

11. Thomas P, Dong J. Binding and activation of the seventransmembrane estrogen receptor GPR30 by environmental estrogens: a potential novel mechanism of endocrine disruption. J. Steroid Biochem. Mol. Biol. 2006; 102: 175-179. doi: 10.1016/j. jsbmb.2006.09.017

12. Thomas P, Pang Y, Filardo EJ, Dong J. Identity of an estrogen membranereceptor coupled to a G protein in human breast cancer cells. Endocrinology. 2005; 146: 624-632.

13. Thomas P,Alyea R, PangY, Peyton C, Dong J, BergAH. Conservedestrogen binding and signaling functions of the G proteincoupled estrogen receptor 1 GPER1 in mammals and fish. Steroids. 2010; 75: 595-602. doi: 10.1016/j.steroids.2009.11.005

14. Pang Y, Thomas P. Progesterone signals through membrane progesterone receptors mPRs in MDA-MB-468 and mPRtransfected MDA-MB-231 breast cancer cells which lack fulllength and N-terminally truncated isoforms of the nuclear progesterone receptor. Steroids. 2011; 76: 921-928. doi: 10.1016/j. steroids.2011.01.008

15. Bologa CG, Revankar CM, Young SM, et al. Virtual and biomolecular screening converge on a selective agonist for GPR30. Nat. Chem. Biol. 2006; 2: 207-212. doi: 10.1038/ nchembio775

16. Alexander SP, Mathie A, Peters JA. Guide to receptors and channels(GRAC). 5th edition. Br J Pharmacol. 2011; 154(Suppl 1): S1-S324. doi: 10.1111/j.1476-5381.2011.01649_1.x

17. Grimont A, Bloch-Faure M, El Abida B, Crambert G. Mapping of sex hormone receptors and their modulators along the nephron of male and female mice. FEBS Lett. 2009; 583: 1644- 1648. doi: 10.1016/j.febslet.2009.04.032

18. Hazell GG, Yao ST, Roper JA, Prossnitz ER, Oā€™Carroll AM, Lolait SJ. Localisation of GPR30, a novel G protein-coupled oestrogen receptor, suggests multiple functions in rodent brain and peripheral tissues. J. Endocrinol. 2009; 202: 223-236. doi: 10.1677/JOE-09-0066

19. Cheng SB, Graeber CT, Quinn JA, Filardo EJ. Retrograde transport of the transmembrane estrogen receptor, G-proteincoupled-receptor-30 GPR30/GPER from the plasma membrane towards the nucleus. Steroids. 2011; 76: 892-896. doi: 10.1016/j. steroids.2011.02.018

20. Lindsey SH, Yamaleyeva LM, Brosnihan KB, Gallagher PE, Chappell MC. Estrogen receptor GPR30 reduces oxidative stress and proteinuria in the salts ensitive female mRen2. Lewis rat. Hypertension. 2011; 58: 665-671. doi: 10.1161/HYPERTENSIONAHA

21. Hofmeister MV, Damkier HH, Christensen BM, et al. 17beta-Estradiol inducesnongenomic effects in renal intercalated cells through G protein-coupled estrogen receptor 1. Am J Physiol Renal Physiol. 2012; 302: F358-F368. doi: 10.1152/ ajprenal.00343.2011

22. Cheng SB, Dong J, Pang Y, et al. Anatomicallocation and redistribution of G protein-coupled estrogen receptor-1 during theestrus cycle in mouse kidney and specific binding to estrogens but notaldosterone. Mol Cell Endocrinol. 2014; 382(2): 950-959. doi: 10.1016/j.mce.2013.11.005

23. Kurt AH, Buyukafsar K. Vasoconstriction induced by G1, a G-protein-coupledoestrogen receptor1 (GPER-1) agonist, in the isolated perfused rat kidney. Eur J Pharmacol. 2013; 702(1-3): 71-78. doi: 10.1016/j.ejphar.2013.01.020

 

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