Published Online
on May 26, 2008

A more recent version of this article appeared on July 1, 2008

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Submitted on August 6, 2007
Revised on August 26, 2007

Hypertension Induces Somatic Cellular Senescence in Rats and Humans by Induction of Cell Cycle Inhibitor p16^INK4a

Jens H. Westhoff; Karl F. Hilgers; Mario P. Steinbach; Andrea Hartner; Bernd Klanke; Kerstin Amann; and Anette Melk^*

From the Division of Pediatric Nephrology (J.H.W., M.P.S., A.M.), University Children's Hospital, Heidelberg, Germany; and the Departments of Nephrology and Hypertension (K.F.H., A.H., B.K.) and Pathology (K.A.), University of Erlangen-Nuremberg, Erlangen, Germany.

^* To whom correspondence should be addressed. E-mail: melk.anette{at}mh-hannover.de.

Abstract—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 phosphor-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.

Key words: target organ damage • kidney • heart • senescence • p16^INK4a expression • cell cycle inhibitor

Related Article:

Treatment-Sensitive Premature Renal and Heart Senescence in Hypertension

Martin W. Bergmann, Laura Zelarayan, and Christina Gehrke
Hypertension 2008 52: 61-62. [Extract] [Full Text] [PDF]

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