Kidney Inter.1999,55,1577-1579

Kidney International,Vol.55(1999),pp.1577–1579

EDITORIAL Estrogen:It’s not just for reproduction any more

Estrogens serve critical roles in the development of given estrogen may vary with different assay systems.For

female secondary sex characteristics and the regulation instance,while E2facilitates endothelial cell angiogenesis

of uterine changes that occur during the menstrual cycle[2],another estrogen metabolite,2-methoxyestradiol,in-

and pregnancy.In addition,a variety of tissues unrelated duces apoptosis in endothelial cells and is anti-angiogenic

to reproductive function contain estrogen-producing[3].Both of these are“estrogen”effects.As another

aromatase activity.It is therefore not surprising that example,tamoxifen,recently found to have“anti-estro-

clinical data demonstrate bene?cial effects of estrogen gen”effects in preventing breast cancer,may have“pro-

on osteoporosis and atherosclerosis in women.These estrogen”effects in decreasing the risk of cardiovascular

?ndings suggest that this hormone has important physio-disease[4].Thus,the effects of estrogen depend upon

logical roles beyond those related to gonadal function.both its metabolism and its targets.

The potential spectrum of such actions has been ex-Several aspects of cellular physiology may explain how

tended by studies indicating that gender may in?uence similar—or even identical—forms of estrogen have var-

the outcome of progressive renal disease.This gender ied impacts on different biological systems.One of these

impact can be positive or negative,perhaps re?ecting is the activation status of the target cell.We have ob-

the effects of several gonadal steroids on the varied path-served that endothelial cells respond differently to E

2 ways for in?ammation,cell migration or proliferation when they are in con?uent cultures than when they are

that mediate different disease models.The experiments actively dividing,are injured or have been exposed to

reported by Silbiger and colleagues in this issue of Kid-stimulatory cytokines[5].This variability would suggest

ney International continue their investigation of a poten-that ER activation serves largely to amplify other signal-

tial role for estrogen in regulating one aspect of this ing pathways that have been activated by concurrent

intricate pathophysiological web,mesangial cell collagen stimuli.In agreement with this proposed model,E

2en-

synthesis[1].The authors show that estrogen increases hances endothelial cell-leukocyte adhesion in response AP-1transcription factor activity that in turn inhibits to tumor necrosis factor(TNF)?,but has no effect on type I collagen gene activation.In order to consider the interleukin-1-stimulated adhesion or on adhesion in the implications of these?ndings for glomerulosclerosis,it absence of TNF?[6].Conversely,other investigators is appropriate for us to review current understanding of have determined that the ability of basic?broblast estrogen receptor(ER)function.Much of the available growth factor(bFGF)to stimulate angiogenesis is abro-data are derived from manipulating transformed cells.gated in ER-de?cient mice[7].The requirement for a

Only recently have investigators begun to examine non-functional ER in this model suggests that E

2/ER acts as

transformed cells,and studies of cells from renal tissue a necessary,permissive cofactor for signals stimulated are extremely rare.The present discussion will thus serve by other mediators.Consistent with this interpretation largely as a guide for future studies related more directly is the observation that the ER forms a transcription to ER function in the kidney.regulatory complex with the p300transcription factor Estrogen is known to interact with a cytoplasmic re-[8]that can be activated by growth factors.

ceptor that can dimerize,undergo phosphorylation and In addition to interaction with other signaling path-be translocated to the nucleus where it acts as a transcrip-ways,estrogen effects may be determined by ER con?g-tion factor;however,our concept of ER actions on tissue uration or type.Different estrogens may bind to recep-function has become increasingly complex.Multiple tors that have been structurally modi?ed by their milieu, forms of estrogen exist.The most abundant circulating or may themselves modify the ER structure,forming estrogen in humans is17?-estradiol(E2).In many bio-transcription regulatory complexes with different af?ni-assays,such as the ability to stimulate endometrial cell ties for gene-promoter sequences or for transcription co-proliferation,E2is the most active estrogen on a molar factors[9].Splice variants of the ER,perhaps similarly basis.However,the measured biological activity of a re?ecting variations in the cellular milieu,have been de-

tected by reverse transcription-polymerase chain reaction

analysis of vascular smooth muscle cells[10].Whether Key words:hormone,aromatose activity,gender and progressive renal

disease,mesangial cell collagen.these variants are expressed at the protein level,or

whether expressed variants have unique biological prop-?1999by the International Society of Nephrology

1577

1578

Editorial

erties,remains to be determined.Finally,the recent dis-notion that estrogen could play a signi?cant regulatory

covery of a distinct gene for a second ER,termed ER?

role.Future studies might address several important

[11],has stimulated intense interest in determining questions.First,the present studies were performed in

whether different receptor gene products mediate differ-

murine cells;since there may be signi?cant species speci-

ent estrogen effects on cells.?city in regulation of gene transcription,con?rmatory

A third determinant of estrogen effects may be“non-

studies in human tissue are important.Second,in many

genomic”mechanisms of ER action.In endothelial cells,diseases,glomerular accumulation of type IV collagen

mitogen-activated protein(MAP)kinase activation by

is at least as important as that of type I collagen,if not

E2is slow(3hours)and is prevented by inhibitors of more so.Can the present results with type I collagen be

protein synthesis,suggesting a classical action of ER on

generalized to all forms of collagen?Third,the present

gene transcription[12].In contrast,MAP kinase activa-experiments evaluated“basal”collagen expression in

tion by E2in breast cancer epithelia is virtually immedi-

cultured cells.Will estrogen also decrease responses to

ate and does not require new protein synthesis[13].pathogenic stimuli?Finally,animal models will ulti-

Endothelial cells also may have non-genomic,ER-medi-

mately determine the clinical signi?cance of these?nd-

ated signaling pathways.For example,bFGF release(as ings.Thus,this report by Silbiger and colleagues provides

opposed to synthesis)by endothelial cells cultured on

a welcome stimulus for additional characterization of a

basement membrane proteins is enhanced by ER activa-regulatory mechanism that is potentially important in

tion,but is not affected by inhibitors of protein synthesis

glomerulosclerosis.

[14].These data suggest that some ER-mediated signals

H.William Schnaper are not mediated through classical transcriptional mech-

Department of Pediatrics,Northwestern University Medical anisms.Several investigators have sought in recent years School,Chicago,Illinois

to de?ne a traditional pathway in which the ER acts as

a cell-surface receptor that works through a classical,ACKNOWLEDGMENTS

second-messenger signaling mechanism[15],but the low

Supported by grants DK49362and DK53576from the National abundance of ER on the cell surface has hampered de-

Institute of Diabetes,Digestive and Kidney Diseases and HL53918?nitive characterization of such a pathway.from the National Heart,Lung and Blood Institute.Susan Hubchak

provided helpful comments on the manuscript.

Together,these?ndings de?ne complex regulatory

mechanisms by which estrogen may alter cell function.

Correspondence to H.William Schnaper,M.D.,Pediatrics W-140 It is apparent that the effects of estrogens on mesangial(Ward12-104),303E.Chicago Ave.,Chicago,Illinois60611-3008,USA.

E-mail:schnaper@https://www.360docs.net/doc/dd5538329.html,

cells will be in?uenced by the spectrum of estrogens that

are present,other stimuli received by the cells,the forms

REFERENCES

of ER that are present,and interacting signaling path-

ways.Thus,considerable work remains in de?ning mes- 1.Silbiger S,Lei J,Neugarten J:Estradiol suppresses type I collagen

synthesis in mesangial cells via activation of AP-1.Kidney Int angial cell estrogen biology.In relating in vitro studies

55:1268–1276,1999

to in vivo conditions,a critical consideration is the con-

2.Morales DE,McGowan KA,Grant DS,Mahashwari S,Bhar-centration of hormone used.E2has been found to have tiya D,Cid MC,Kleinman HK,Schnaper HW:Estrogens promote

angiogenic activity in human umbilical vein endothelial cells in bifunctional effects on gene transcription in some sys-

vitro and in a murine model.Circulation91:755–763,1995 tems,with low doses being stimulatory and higher doses

3.Yue T-L,Wang X,Louden CS,Gupta S,Pillarisetti K,Gu being inhibitory.The level of circulating E2in women J-L,Hart TK,Lysko PG,Feuerstein GZ:2-methoxyestradiol,an

endogenous estrogen metabolite,induces apoptosis in endothelial peaks during ovulation at just over1n m(300to500pg/

cells and inhibits angiogenesis:Possible role for stress-activated ml),and levels are slightly lower during the luteal phase

protein kinase signaling pathway and Fas expression.Mol Pharma-of the menstrual cycle[16].In the present paper,the col51:951–962,1997

minimal inhibitory dose of E2was slightly higher than

4.Rutqvist LE,Mattson A:Cardiac and thrombolic morbidity

among postmenopausal women with early-stage breast cancer in physiological levels,and inhibition was greater when the

a randomized trial of adjuvant tamoxifen.J Natl Cancer Inst dose was signi?cantly higher.We do not know the local85:1398–1406,1993

levels of E2in the glomerulus.Could there be suf?cient

5.Schnaper HW,McGowan KA,Hubchak SC,Cid MC,Kim-

Schulze S:Endothelial cells,estrogen and angiogenesis,in Ernst aromatase to raise E2levels beyond systemic concentra-

Schering Research Foundation Workshop21:Nitric Oxide,Cyto-tions?If so,this would raise the possibility of a novel chromes P450and Sexual Steroids,edited by Habenicht U-F,Lan-

local protective mechanism.Thus,a starting point for in

caster JR,Berlin,Springer-Verlag,1997,pp283–301

6.Cid MC,Kleinman HK,Grant DS,Schnaper HW,Fauci AS, vivo correlation might be to determine the nature and

Hoffman GS:Estradiol enhances leukocyte binding to tumor ne-extent of glomerular aromatase activity.crosis factor(TNF)-stimulated endothelial cells via an increase in

Another perspective for these studies involves the re-

TNF-induced adhesion molecules E-selectin,intercellular adhesion

molecule type1and vascular cell adhesion molecule type1.J Clin lationship of the authors’results to clinical disease.Al-

Invest93:17–25,1994

though there are multiple pathways of glomerular matrix7.Johns A,Freay AD,Fraser W,Korach KS,Rubanyi GM:Disrup-accumulation,this cellular model strongly supports the

tion of estrogen receptor gene prevents17beta estradiol-induced

Editorial1579 angiogenesis in transgenic mice.Endocrinology137:4511–4513,mitogen-activated protein kinase(ERK1/2)activity in endothelial

cells via an autocrine loop involving basic?broblast growth factor.

1996.

Circulation98:413–421,1998

8.Kraus WL,Kadonaga JT:p300and estrogen receptor coopera-

13.Migliaccio A,Di Domenico M,Castoria G,Falco Ad,Bontempo

tively activate transcription via differential enhancement of initia-

P,Nola E,Auricchio F:Tyrosine kinase/p21ras/MAP-kinase path-tion and reinitiation.Genes Dev12:331–342,1998

way activation by estradiol-receptor complex in MCF-7cells.

9.McDonnell DP,Clemm DL,Hermann T,Goldman ME,Pike

EMBO J15:1292–1300,1996

JW:Analysis of estrogen receptor function in vitro reveals three

14.Albuquerque MLC,Akiyama SK,Schnaper HW:Human coro-

distinct classes of antiestrogens.Mol Endocrinol9:659–669,1995

nary artery endothelial cell secretion of basic?broblast growth 10.Karas RH,Baur WE,van Eickles M,Mendelsohn ME:Human factor is enhanced by matrix proteins,17?-estradiol and a PKC

vascular smooth muscle cells express an estrogen receptor isoform.signaling pathway.Exp Cell Res245:163–169,1998

FEBS Lett377:103–108,199515.Pappas TC,Gametchu B,Watson C:Membrane estrogen recep-11.Kuiper GGMJ,Enmark E,Pelto-Huikko M,Nilsson S,Gustafs-tors identi?ed by multiple antibody labeling and impeded-ligand

son J-A:Cloning of a novel estrogen receptor expressed in rat binding.FASEB J9:404–410,1995

prostate and ovary.Proc Natl Acad Sci USA93:5925–5930,199616.Naftolin F,Tolis G:Neuroendocrine regulation of the menstrual 12.Kim-Schulze S,Lowe WL Jr,Schnaper HW:Estrogen induces

cycle.Clin Obstetr Gynecol21:17–29,1978