title: Hypertension induces somatic cellular senescence in rats and humans by induction of cell cycle inhibitor p16INK4a.
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 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.
authors.affiliation: Division of Pediatric Nephrology, University Children's Hospital, Heidelberg, Germany.
authors.forename: Jens H
authors.initials: JH
authors.lastname: Westhoff
authors.forename: Karl F
authors.initials: KF
authors.lastname: Hilgers
authors.forename: Mario P
authors.initials: MP
authors.lastname: Steinbach
authors.forename: Andrea
authors.initials: A
authors.lastname: Hartner
authors.forename: Bernd
authors.initials: B
authors.lastname: Klanke
authors.forename: Kerstin
authors.initials: K
authors.lastname: Amann
authors.forename: Anette
authors.initials: A
authors.lastname: Melk
mesh_terms: D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D030801:Animals, Genetically Modified; D000959:Antihypertensive Agents / Q000494:pharmacology / Q000627:therapeutic use; D001794:Blood Pressure / Q000187:drug effects; D016922:Cellular Senescence / Q000187:drug effects; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics / Q000378:metabolism*; D003900:Desoxycorticosterone / Q000494:pharmacology; D006352:Heart Ventricles / Q000378:metabolism / Q000473:pathology; D006801:Humans; D006830:Hydralazine / Q000494:pharmacology / Q000627:therapeutic use; D006852:Hydrochlorothiazide / Q000494:pharmacology / Q000627:therapeutic use; D006977:Hypertension, Renal / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D007668:Kidney / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D019808:Losartan / Q000494:pharmacology / Q000627:therapeutic use; D051379:Mice; D000451:Mineralocorticoid Receptor Antagonists / Q000494:pharmacology; D009400:Nephrosclerosis / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D012083:Renin / Q000235:genetics; D012110:Reserpine / Q000494:pharmacology / Q000627:therapeutic use; D013148:Spironolactone / Q000494:pharmacology / Q000627:therapeutic use; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D000959:Antihypertensive Agents; D019941:Cyclin-Dependent Kinase Inhibitor p16; D000451:Mineralocorticoid Receptor Antagonists; D012333:RNA, Messenger; C473112:Ren2 protein, mouse; D006852:Hydrochlorothiazide; D006830:Hydralazine; D013148:Spironolactone; D003900:Desoxycorticosterone; D012110:Reserpine; D048051:p38 Mitogen-Activated Protein Kinases; D012083:Renin; D019808:Losartan