Hypertension Induces Somatic Cellular Senescence in Rats and Humans by Induction of Cell Cycle Inhibitor p16INK4a

被引：119

作者：

Westhoff, Jens H. ^{[1
]}

Hilgers, Karl F. ^{[2
]}

Steinbach, Mario P. ^{[1
]}

Hartner, Andrea ^{[2
]}

Klanke, Bernd ^{[2
]}

Amann, Kerstin ^{[3
]}

Melk, Anette ^{[1
]}

机构：

[1] Univ Childrens Hosp, Div Pediat Nephrol, Heidelberg, Germany

[2] Univ Erlangen Nurnberg, Dept Hypertens & Nephrol, Erlangen, Germany

[3] Univ Erlangen Nurnberg, Dept Pathol, Erlangen, Germany

来源：

HYPERTENSION | 2008年 / 52卷 / 01期

关键词：

target organ damage; kidney; heart; senescence; p16(INK4a) expression; cell cycle inhibitor;

D O I：

10.1161/HYPERTENSIONAHA.107.099432

中图分类号：

R6 [外科学];

学科分类号：

1002 ; 100210 ;

摘要：

There is increasing evidence for a role of somatic cellular senescence in physiological aging but also in injury and disease. Cell cycle inhibitor p16(INK4a) is the key mediator for stress and aberrant signaling induced senescence. Here we report that elevated blood pressure markedly induced p16(INK4a) expression in rat kidneys and hearts, as well as in human kidneys. In kidneys from deoxycorticosterone acetate-salt-treated rats, p16(INK4a) induction was found in tubular, glomerular, interstitial, and vascular cells and correlated with the typical histopathologic features of hypertensive target organ damage. p16(INK4a) expression also correlated with phospho-p38, a positive upstream regulator of p16(INK4a) expression. In left ventricles, increased p16(INK4a) expression was found in myocardium and cardiac arteries. Antihypertensive medication consistent of hydrochlorothiazide, hydralazine, and reserpine ameliorated the histopathologic changes and attenuated p16(INK4a) expression in kidneys of deoxycorticosterone acetate-salt-treated rats. Nonantihypertensive administration of spironolactone also reduced kidney damage and p16(INK4a) expression. p16(INK4a) induction was further observed in kidneys from hypertensive transgenic rats heterozygous for the mouse Ren-2 gene and was prevented by the angiotensin II type 1 receptor blocker losartan. In human kidney biopsies showing hypertensive nephrosclerosis, increased p16(INK4a) expression was found compared with age-matched normotensive control subjects. Thus, hypertension induces cellular senescence via p16(INK4a), possibly through p38, thereby contributing to hypertensive target organ damage. This detrimental effect can be overcome by different therapeutic drug strategies. (Hypertension. 2008;52:123-129.)

引用

页码：123 / 129

页数：7

共 31 条

[1] Hypertensive end-organ damage and premature mortality are p38 mitogen-activated protein kinase-dependent in a rat model of cardiac hypertrophy and dysfunction [J].

Behr, TM ;

Nerurkar, SS ;

Nelson, AH ;

Coatney, RW ;

Woods, TN ;

Sulpizio, A ;

Chandra, S ;

Brooks, DP ;

Kumar, S ;

Lee, JC ;

Ohlstein, EH ;

Angermann, CE ;

Adams, JL ;

Sisko, J ;

Sackner-Bernstein, JD ;

Willette, RN .

CIRCULATION, 2001, 104 (11) :1292-1298

[2] Telomeres and human disease: Ageing, cancer and beyond [J].

Blasco, MA .

NATURE REVIEWS GENETICS, 2005, 6 (08) :611-622

[3] Inactivation of the Wip1 phosphatase inhibits mammary tumorigenesis through p38 MAPK-mediated activation of the p16Ink4a-p19Arf pathway [J].

Bulavin, DV ;

Phillips, C ;

Nannenga, B ;

Timofeev, O ;

Donehower, LA ;

Anderson, CW ;

Appella, E ;

Fornace, AJ .

NATURE GENETICS, 2004, 36 (04) :343-350

[4] c-Src-dependent nongenomic signaling responses to aldosterone are increased in vascular myocytes from spontaneously hypertensive rats [J].

Callera, GE ;

Montezano, ACI ;

Yogi, A ;

Tostes, RC ;

He, Y ;

Schiffrin, EL ;

Touyz, RM .

HYPERTENSION, 2005, 46 (04) :1032-1038

[5] Cellular senescence: when bad things happen to good cells [J].

Campisi, Judith ;

di Fagagna, Fabrizio d'Adda .

NATURE REVIEWS MOLECULAR CELL BIOLOGY, 2007, 8 (09) :729-740

[6] Senescence and death of primitive cells and myocytes lead to premature cardiac aging and heart failure [J].

Chimenti, C ;

Kajstura, J ;

Torella, D ;

Urbanek, K ;

Heleniak, H ;

Colussi, C ;

Di Meglio, F ;

Nadal-Ginard, B ;

Frustaci, A ;

Leri, A ;

Maseri, A ;

Anversa, P .

CIRCULATION RESEARCH, 2003, 93 (07) :604-613

[7] Specific MAP-kinase blockade protects against renal damage in homozygous TGR(mRen2)27 rats [J].

de Borst, MH ;

Navis, G ;

de Boer, RA ;

Huitema, S ;

Vis, LM ;

van Gilst, WH ;

van Goor, H .

LABORATORY INVESTIGATION, 2003, 83 (12) :1761-1770

[8] Mechanisms of disease:: the role of aldosterone in kidney damage and clinical benefits of its blockade [J].

Del Vecchio, Lucia ;

Procaccio, Mirella ;

Vigano, Sara ;

Cusi, Daniele .

NATURE CLINICAL PRACTICE NEPHROLOGY, 2007, 3 (01) :42-49

[9] Telomere biology and cardiovascular disease [J].

Fuster, Jose J. ;

Andres, Vicente .

CIRCULATION RESEARCH, 2006, 99 (11) :1167-1180

[10] Renoprotective effect of a dopamine D3 receptor antagonist in experimental type II diabetes [J].

Gross, MLP ;

Koch, A ;

Mühlbauer, B ;

Adamczak, M ;

Ziebart, H ;

Drescher, K ;

Gross, G ;

Berger, I ;

Amann, KU ;

Ritz, E .

LABORATORY INVESTIGATION, 2006, 86 (03) :262-274

← 1 2 3 4 →