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Open Access 01-12-2011 | Research article

Renin angiotensin system and gender differences in dopaminergic degeneration

Authors: Ana I Rodriguez-Perez, Rita Valenzuela, Belen Joglar, Pablo Garrido-Gil, Maria J Guerra, Jose L Labandeira-Garcia

Published in: Molecular Neurodegeneration | Issue 1/2011

Abstract

Background

There are sex differences in dopaminergic degeneration. Men are approximately two times as likely as premenopausal women of the same age to develop Parkinson's disease (PD). It has been shown that the local renin angiotensin system (RAS) plays a prominent role in sex differences in the development of chronic renal and cardiovascular diseases, and there is a local RAS in the substantia nigra and dopaminergic cell loss is enhanced by angiotensin via type 1 (AT1) receptors.

Results

In the present study, we observed that intrastriatal injection of 6-hydroxydopamine induced a marked loss of dopaminergic neurons in the substantia nigra of male rats, which was significantly higher than the loss induced in ovariectomized female rats given estrogen implants (i.e. rats with estrogen). However, the loss of dopaminergic neurons was significantly lower in male rats treated with the AT1 antagonist candesartan, and similar to that observed in female rats with estrogen. The involvement of the RAS in gender differences in dopaminergic degeneration was confirmed with AT1a-null mice lesioned with the dopaminergic neurotoxin MPTP. Significantly higher expression of AT1 receptors, angiotensin converting enzyme activity, and NADPH-oxidase complex activity, and much lower levels of AT2 receptors were observed in male rats than in female rats with estrogen.

Conclusions

The results suggest that brain RAS plays a major role in the increased risk of developing PD in men, and that manipulation of brain RAS may be an efficient approach for neuroprotective treatment of PD in men, without the feminizing effects of estrogen.

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Mayeux R, Marder K, Cote LJ, Denaro J, Hemenegildo N, Mejia H, Tang MX, Lantigua R, Wilder D, Gurland B, et al: The frequency of idiopathic Parkinson's disease by age, ethnic group, and sex in northern Manhattan, 1988-1993. Am J Epidemiol. 1995, 142: 820-827.PubMed

Baldereschi M, Di Carlo A, Rocca WA, Vanni P, Maggi S, Perissinotto E, Grigoletto F, Amaducci L, Inzitari D: Parkinson's disease and parkinsonism in a longitudinal study: two-fold higher incidence in men. ILSA Working Group. Italian Longitudinal Study on Aging. Neurology. 2000, 5: 1358-1363.CrossRef

Van Den Eeden SK, Tanner CM, Bernstein AL, Fross RD, Leimpeter A, Bloch DA, Nelson LM: Incidence of Parkinson's disease: variation by age, gender, and race/ethnicity. Am J Epidemiol. 2003, 157: 1015-1022. 10.1093/aje/kwg068.PubMedCrossRef

González-Hernández T, Cruz-Muros I, Afonso-Oramas D, Salas-Hernandez J, Castro-Hernandez J: Vulnerability of mesostriatal dopaminergic neurons in Parkinson's disease. Front Neuroanat. 2010, 4: 140-PMID:21079748PubMedPubMedCentralCrossRef

Seshiah PN, Weber DS, Rocic P, Valppu L, Taniyama Y, Griendling KK: Angiotensin II stimulation of NAD(P)H oxidase activity: upstream mediators. Circ Res. 2002, 91: 406-413. 10.1161/01.RES.0000033523.08033.16.PubMedCrossRef

Cai H, Griendling KK, Harrison DG: The vascular NAD(P)H oxidases as therapeutic targets in cardiovascular diseases. Trends PharmacolSci. 2003, 24: 471-478. 10.1016/S0165-6147(03)00233-5.CrossRef

Touyz RM, Chen X, Tabet F, Yao G, He G, Quinn MT, Pagano PJ, Schiffrin EL: Expression of a functionally active gp91phox-containing neutrophil-type NAD(P)H oxidase in smooth muscle cells from human resistance arteries: regulation by angiotensin II. Circ Res. 2002, 14: 1205-1213.CrossRef

Babior B: NADPH oxidase: An update. Blood. 1999, 93: 1464-1476.PubMed

Babior BM: NADPH oxidase. Curr Opin Immunol. 2004, 16: 42-47. 10.1016/j.coi.2003.12.001.PubMedCrossRef

10.

Fischer M, Baessler A, Schunkert H: Renin angiotensin system and gender differences in the cardiovascular system. Cardiovasc Res. 2002, 53: 672-677. 10.1016/S0008-6363(01)00479-5.PubMedCrossRef

11.

McGuire BB, Watson RW, Pérez-Barriocanal F, Fitzpatrick JM, Docherty NG: Gender differences in the renin-angiotensin and nitric oxide systems: relevance in the normal and diseased kidney. Kidney Blood Press Res. 2007, 30: 67-80. 10.1159/000099150.PubMedCrossRef

12.

Sandberg K, Ji H: Sex and the renin angiotensin system: implications for gender differences in the progression of kidney disease. Adv Ren Replace Ther. 2003, 10: 15-23. 10.1053/jarr.2003.50006.PubMedCrossRef

13.

Liu J, Ji H, Zheng W, Wu X, Zhu JJ, Arnold AP, Sandberg K: Sex differences in renal angiotensin converting enzyme 2 (ACE2) activity are 17β-oestradiol-dependent and sex chromosome-independent. Biol Sex Differ. 2010, 1: 6-10.1186/2042-6410-1-6.PubMedPubMedCentralCrossRef

14.

Baiardi G, Macova M, Armando I, Ando H, Tyurmin D, Saavedra JM: Estrogen upregulates renal angiotensin II AT1 and AT2 receptors in the rat. Regul Pept. 2005, 124: 7-17. 10.1016/j.regpep.2004.06.021.PubMedCrossRef

15.

Sullivan JC: Sex and the renin-angiotensin system: inequality between the sexes in response to RAS stimulation and inhibition. Am J Physiol Regul Integr Comp Physiol. 2008, 294: R1220-1226. 10.1152/ajpregu.00864.2007.PubMedCrossRef

16.

Chen J, Yang S, Hu S, Choudhry MA, Bland KI, Chaudry IH: Estrogen prevents intestinal inflammation after trauma-hemorrhage via downregulation of angiotensin II and angiotensin II subtype I receptor. Am J Physiol Gastrointest Liver Physiol. 2008, 295: G1131-1137. 10.1152/ajpgi.90443.2008.PubMedPubMedCentralCrossRef

17.

Dean SA, Tan J, O'Brien ER, Leenen FH: 17beta-estradiol downregulates tissue angiotensin-converting enzyme and ANG II type 1 receptor in female rats. Am J Physiol Regul Integr Comp Physiol. 2004, 288: R759-766. 10.1152/ajpregu.00595.2004.PubMedCrossRef

18.

Nickenig G, Bäumer AT, Grohè C, Kahlert S, Strehlow K, Rosenkranz S, Stäblein A, Beckers F, Smits JF, Daemen MJ, Vetter H, Böhm M: Estrogen modulates AT1 receptor gene expression in vitro and in vivo. Circulation. 1998, 97: 2197-2201.PubMedCrossRef

19.

Ojeda NB, Royals TP, Black JT, Dasinger JH, Johnson JM, Alexander BT: Enhanced sensitivity to acute angiotensin II is testosterone dependent in adult male growth-restricted offspring. Am J Physiol Regul Integr Comp Physiol. 2010, 298: R1421-1427. 10.1152/ajpregu.00096.2010.PubMedPubMedCentralCrossRef

20.

Henriques T, Zhang X, Yiannikouris FB, Daugherty A, Cassis LA: Androgen increases AT1a receptor expression in abdominal aortas to promote angiotensin II-induced AAAs in apolipoprotein E-deficient mice. Arterioscler Thromb Vasc Biol. 2008, 28: 1251-1256. 10.1161/ATVBAHA.107.160382.PubMedPubMedCentralCrossRef

21.

McKinley MJ, Albiston AL, Allen AM, Mathai ML, May CN, McAllen RM, Oldfield BJ, Mendelsohn FAO, Chai S: The brain reenin-angiotensin system: location and physiological roles. Int J Biochem Cell Biol. 2003, 35: 901-918. 10.1016/S1357-2725(02)00306-0.PubMedCrossRef

22.

Saavedra JM: Brain angiotensin II: new developments, unanswered questions and therapeutic opportunities. Cell Mol Neurobiol. 2005, 25: 485-512. 10.1007/s10571-005-4011-5.PubMedCrossRef

23.

Rey P, Lopez-Real A, Sanchez-Iglesias S, Muñoz A, Soto-Otero R, Labandeira-Garcia JL: Angiotensin type-1-receptor antagonists reduce 6-hydroxydopamine toxicity for dopaminergic neurons. Neurobiol Aging. 2007, 28: 555-567. 10.1016/j.neurobiolaging.2006.02.018.PubMedCrossRef

24.

Rodriguez-Pallares J, Rey P, Parga JA, Muñoz A, Guerra MJ, Labandeira-Garcia JL: Brain angiotensin enhances dopaminergic cell death via microglial activation and NADPH-derived ROS. Neurobiol Dis. 2008, 31: 58-73. 10.1016/j.nbd.2008.03.003.PubMedCrossRef

25.

Joglar B, Rodriguez-Pallares J, Rodríguez-Perez AI, Rey P, Guerra MJ, Labandeira-Garcia JL: The inflammatory response in the MPTP model of Parkinson's disease is mediated by brain angiotensin: relevance to progression of the disease. J Neurochem. 2009, 109: 656-669. 10.1111/j.1471-4159.2009.05999.x.PubMedCrossRef

26.

Lloyd GW, Patel NR, McGing E, Cooper AF, Brennand-Roper D, Jackson G: Does angina vary with the menstrual cycle in women with premenopausal coronary artery disease?. Heart. 2000, 84: 189-192. 10.1136/heart.84.2.189.PubMedPubMedCentralCrossRef

27.

Mills PJ, Ziegler MG, Nelesen RA, Kennedy BP: The effects of the menstrual cycle, race, and gender on adrenergic receptors and agonists. Clin Pharmacol Ther. 1996, 60: 99-104. 10.1016/S0009-9236(96)90172-1.PubMedCrossRef

28.

Li JM, Shah AM: Mechanism of endothelial cell NADPH oxidase activation by angiotensin II. Role of the p47phox subunit. J Biol Chem. 2003, 278: 12094-12100. 10.1074/jbc.M209793200.PubMedCrossRef

29.

Rueckschloss U, Quinn MT, Holtz J, Morawietz H: Dose-dependent regulation of NAD(P)H oxidase expression by angiotensin II in human endothelial cells: protective effect of angiotensin II type 1 receptor blockade in patients with coronary artery disease. Arterioscler Thromb Vasc Biol. 2002, 22: 1845-1851. 10.1161/01.ATV.0000035392.38687.65.PubMedCrossRef

30.

Gao HM, Liu B, Zhang W, Hong JS: Synergistic dopaminergic neurotoxicity of MPTP and inflammogen lipopolysaccharide: relevance to the etiology of Parkinson's disease. FASEB J. 2003, 17: 1957-1959.PubMed

31.

Andersen JK: Oxidative stress in neurodegeneration: cause or consequence. Nat Med. 2004, 10: S18-25. 10.1038/nrn1434.PubMedCrossRef

32.

Wu DC, Jackson-Lewis V, Vila M, Tieu K, Teismann P, Choi DK, Przedborski S: Blockade of microglial activation is neuroprotective in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson disease. J Neurosci. 2002, 22: 1763-1771.PubMed

33.

Wu D, Teisman P, Tieu K, Vila M, Jackson-Lewis V, Ischiropoulos H, Przedborski S: NADPH oxidase mediates oxidative stress in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine model of Parkinson¨s disease. Proc Natl Acad Sci USA. 2003, 100: 6145-6150. 10.1073/pnas.0937239100.PubMedPubMedCentralCrossRef

34.

Qin L, Liu Y, Wang T, Wei SJ, Block ML, Wilson B, Liu B, Hong JS: NADPH oxidase mediates lipopolysaccharide-induced neurotoxicity and proinflammatory gene expression in activated microglia. J Biol Chem. 2004, 279: 1415-1421.PubMedCrossRef

35.

Sohn HY, Raff U, Hoffmann A, Gloe T, Heermeier K, Galle J, Pohl U: Differential role of angiotensin II receptor subtypes on endothelial superoxide formation. Br J Pharmacol. 2000, 131: 667-672. 10.1038/sj.bjp.0703566.PubMedPubMedCentralCrossRef

36.

Lu Q, Zhu YZ, Wong PT: Neuroprotective effects of candesartan against cerebral ischemia in spontaneously hypertensive rats. Neuroreport. 2005, 16: 1963-1967. 10.1097/01.wnr.0000187636.13147.cd.PubMedCrossRef

37.

Hamai M, Iwai M, Ide A, Tomochika H, Tomono Y, Mogi M, Horiuchi M: Comparison of inhibitory action. Neuropharmacology. 2006, 51: 822-828. 10.1016/j.neuropharm.2006.05.029.PubMedCrossRef

38.

Rodriguez-Pallares J, Parga JA, Muñoz A, Rey P, Guerra MJ, Labandeira-Garcia JL: Mechanism of 6-hydroxydopamine neurotoxicity: the role of NADPH oxidase and microglial activation in 6-hydroxydopamine-induced degeneration of dopaminergic neurons. J Neurochem. 2007, 103: 145-156.PubMed

39.

Suzuki S, Brown CM, Dela Cruz CD, Yang E, Bridwell DA, Wise PM: Timing of estrogen therapy after ovariectomy dictates the efficacy of its neuroprotective and antiinflammatory actions. Proc Natl Acad Sci USA. 2007, 104: 6013-6018. 10.1073/pnas.0610394104.PubMedPubMedCentralCrossRef

40.

Turgeon JL, Carr MC, Maki PM, Mendelsohn ME, Wise PM: Complex actions of sex steroids in adipose tissue, the cardiovascular system, and brain: Insights from basic science and clinical studies. Endocr Rev. 2006, 27: 575-605. 10.1210/er.2005-0020.PubMedCrossRef

41.

Morale MC, Serra PA, L'episcopo F, Tirolo C, Caniglia S, Testa N, Gennuso F, Giaquinta G, Rocchitta G, Desole MS, Miele E, Marchetti B: Estrogen, neuroinflammation and neuroprotection in Parkinson's disease: glia dictates resistance versus vulnerability to neurodegeneration. Neuroscience. 2006, 138: 869-878. 10.1016/j.neuroscience.2005.07.060.PubMedCrossRef

42.

Tripanichkul W, Sripanichkulchai K, Finkelstein DI: Estrogen down-regulates glial activation in male mice following 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine intoxication. Brain Res. 2006, 1084: 28-37. 10.1016/j.brainres.2006.02.029.PubMedCrossRef

43.

Xue B, Zhao Y, Johnson AK, Hay M: Central estrogen inhibition of angiotensin II-induced hypertension in male mice and the role of reactive oxygen species. Am J Physiol Heart Circ Physiol. 2008, 295: H1025-1032. 10.1152/ajpheart.00021.2008.PubMedPubMedCentralCrossRef

44.

Ito K, Hirooka Y, Kimura Y, Sagara Y, Sunagawa K: Ovariectomy augments hypertension through rho-kinase activation in the brain stem in female spontaneously hypertensive rats. Hypertension. 2006, 48: 651-657. 10.1161/01.HYP.0000238125.21656.9e.PubMedCrossRef

45.

Song J, Kost CK, Martin DS: Androgens potentiate renal vascular responses to angiotensin II via amplification of the Rho kinase signaling pathway. Cardiovasc Res. 2006, 72: 456-463. 10.1016/j.cardiores.2006.09.007.PubMedCrossRef

46.

de Gasparo M, Catt KJ, Inagami T, Wright JW, Unger T: International union of pharmacology. XXIII. The angiotensin II receptors. Pharmacol Rev. 2000, 52: 415-472.PubMed

47.

Correa FM, Viswanathan M, Ciuffo GM, Tsutsumi K, Saavedra JM: Kidney angiotensin II receptors and converting enzyme in neonatal and adult Wistar-Kyoto and spontaneously hypertensive rats. Peptides. 1995, 16: 19-24. 10.1016/0196-9781(94)00150-5.PubMedCrossRef

48.

Ozono R, Wang ZQ, Moore AF, Inagami T, Siragy HM, Carey RM: Expression of the subtype 2 angiotensin (AT2) receptor protein in rat kidney. Hypertension. 1997, 30: 1238-1246.PubMedCrossRef

49.

Wu L, Iwai M, Nakagami H, Li Z, Chen R, Suzuki J, Akishita M, de Gasparo M, Horiuchi M: Roles of angiotensin II type 2 receptor stimulation associated with selective angiotensin II type 1 receptor blockade with valsartan in the improvement of inflammation-induced vascular injury. Circulation. 2001, 104: 2716-2721. 10.1161/hc4601.099404.PubMedCrossRef

50.

Villar-Cheda B, Valenzuela R, Rodriguez-Perez AI, Guerra MJ, Labandeira-Garcia JL: Aging-related changes in the nigral angiotensin system enhances proinflammatory and pro-oxidative markers and 6-OHDA-induced dopaminergic degeneration. Neurobiol Aging. 2010, PMID:20888078

51.

Villar-Cheda B, Rodríguez-Pallares J, Muñoz A, Valenzuela R, Guerra MJ, Baltatu OC, Labandeira-Garcia JL: Nigral and striatal regulation of angiotensin receptor expression by dopamine and angiotensin in rodents: implications for progression of Parkinson's disease. Eur J Neurosci. 2010, 32: 1695-1706. 10.1111/j.1460-9568.2010.07448.x.PubMedCrossRef

52.

Zeng C, Liu Y, Wang Z, He D, Huang L, Yu P, Zheng S, Jones JE, Asico LD, Hopfer U, Eisner GM, Felder RA, Jose PA: Activation of D3 dopamine receptor decreases angiotensin II type 1 receptor expression in rat renal proximal tubule cells. Circ Res. 2006, 99: 494-500. 10.1161/01.RES.0000240500.96746.ec.PubMedCrossRef

53.

Khan F, Spicarová Z, Zelenin S, Holtbäck U, Scott L, Aperia A: Negative reciprocity between angiotensin II type 1 and dopamine D1 receptors in rat renal proximal tubule cells. Am J Physiol Renal Physiol. 2008, 295: F1110-1116. 10.1152/ajprenal.90336.2008.PubMedCrossRef

54.

Gildea JJ: Dopamine and angiotensin as renal counterregulatory systems controlling sodium balance. Curr Opin Nephrol Hypertens. 2009, 18: 28-32. 10.1097/MNH.0b013e32831a9e0b.PubMedPubMedCentralCrossRef

55.

Sugaya T, Nishimatsu S, Tanimoto K, Takimoto E, Yamagishi T, Imamura K, Goto S, Imaizumi K, Hisada Y, Otsuka A, et al: Angiotensin II type 1a receptor-deficient mice with hypotension and hyperreninemia. J Biol Chem. 1995, 270: 18719-18722. 10.1074/jbc.270.32.18719.PubMedCrossRef

56.

Paxinos G, Watson C: The rat brain in stereotaxic coordinates. 1985, New York: Academic Press

57.

Dziuk PJ, Cook B: Passage of steroids through silicone rubber. Endocrinology. 1966, 78: 208-211. 10.1210/endo-78-1-208.PubMedCrossRef

58.

Febo M, Ferris CF, Segarra AC: Estrogen influences cocaine-induced blood oxygen level-dependent signal changes in female rats. J Neurosci. 2005, 25: 1132-1136. 10.1523/JNEUROSCI.3801-04.2005.PubMedCrossRef

59.

Rodriguez-Perez AI, Valenzuela R, Villar-Cheda B, Guerra MJ, Lanciego JL, Labandeira-Garcia JL: Estrogen and angiotensin interaction in the substantia nigra. Relevance to postmenopausal Parkinson's disease. Exp Neurol. 2010, 224: 517-26. 10.1016/j.expneurol.2010.05.015.PubMedCrossRef

60.

Mannino CA, South SM, Inturrisi CE, Quinones-Jenab V: Pharmacokinetics and effects of 17beta-estradiol and progesterone implants in ovariectomized rats. J Pain. 2005, 6: 809-816. 10.1016/j.jpain.2005.07.007.PubMedCrossRef

61.

Fugger HN, Foster TC, Gustafsson J, Rissman EF: Novel effects of estradiol and estrogen receptor alpha and beta on cognitive function. Brain Res. 2000, 883: 258-264. 10.1016/S0006-8993(00)02993-0.PubMedCrossRef

62.

Unger T: Inhibiting angiotensin receptors in the brain: possible therapeutic implications. Curr Med Res Opin. 2003, 19: 449-451. 10.1185/030079903125001974.PubMedCrossRef

63.

Przedborski S, Levivier M, Jiang H, Ferreira M, Jackson-Lewis V, Donaldson D, Togasaki DM: Dose-dependent lesions of the dopaminergic nigrostriatal pathway induced by intrastriatal injection of 6-hydroxydopamine. Neuroscience. 1995, 67: 631-647. 10.1016/0306-4522(95)00066-R.PubMedCrossRef

64.

Sauer H, Oertel WH: Progressive degeneration of nigrostriatal dopamine neurons following intrastriatal terminal lesions with 6-hydroxydopamine: a combined retrograde tracing and immunohistochemical study in the rat. Neuroscience. 1994, 59: 401-415. 10.1016/0306-4522(94)90605-X.PubMedCrossRef

65.

Hemming ML, Selkoe DJ, Farris W: Effects of prolonged angiotensin-converting enzyme inhibitor treatment on amyloid β-protein metabolism in mouse models of Alzheimer disease. Neurobiol Dis. 2007, 26: 273-281. 10.1016/j.nbd.2007.01.004.PubMedPubMedCentralCrossRef

66.

Griendling KK, Minieri CA, Ollerenshaw JD, Alexander RW: Angiotensin II stimulates NADH and NADPH oxidase activity in cultured vascular smooth muscle cells. Circ Res. 1994, 74: 1141-1148.PubMedCrossRef

67.

Hong H, Zeng JS, Kreulen DL, Kaufman DI, Chen AF: Atorvastatin protects against cerebral infarction via inhibition of NADPH oxidase-derived superoxide in ischemic stroke. Am J Physiol Heart Circ Physiol. 2006, 291: H2210-2215. 10.1152/ajpheart.01270.2005.PubMedCrossRef

68.

Gundersen HJG, Bendsen TF, Korbo L, Marcussen N, Moller A, Nielsen K: Some new, simple and efficient stereological methods and their use in pathological research and diagnosis. APIMS. 1988, 96: 379-394. 10.1111/j.1699-0463.1988.tb05320.x.CrossRef

Title: Renin angiotensin system and gender differences in dopaminergic degeneration
Authors: Ana I Rodriguez-Perez
Rita Valenzuela
Belen Joglar
Pablo Garrido-Gil
Maria J Guerra
Jose L Labandeira-Garcia
Publication date: 01-12-2011
Publisher: BioMed Central
Published in: Molecular Neurodegeneration / Issue 1/2011
Electronic ISSN: 1750-1326
DOI: https://doi.org/10.1186/1750-1326-6-58

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Renin angiotensin system and gender differences in dopaminergic degeneration

Abstract

Background

Results

Conclusions

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Results

Conclusions

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