Senescent renal epithelia promote fibrosis and functional loss after injury, whereas depletion improves regeneration in aged or irradiated kidneys.

Long-term graft survival after kidney transplantation remains unsatisfactory and unpredictable. Interstitial fibrosis and tubular atrophy are major contributors to late graft loss; features of tubular cell senescence, such as increased p16^INK4a expression, associate with these tubulointerstitial changes, but it is unknown whether the relationship is causal. Here, loss of the INK4a locus in mice, which allows escape from p16^INK4a-dependent senescence, significantly reduced interstitial fibrosis and tubular atrophy and associated with improved renal function, conservation of nephron mass, and transplant survival. Compared with wild-type controls, kidneys from INK4a^−/− mice developed significantly less interstitial fibrosis and tubular atrophy after ischemia-reperfusion injury. Consistently, mice that received kidney transplants from INK4a/ARF^−/− donors had significantly better survival 21 days after life-supporting kidney transplantation and developed less tubulointerstitial changes. This correlated with higher proliferative rates of tubular cells and significantly fewer senescent cells. Taken together, these data suggest a pathogenic role of renal cellular senescence in the development of interstitial fibrosis and tubular atrophy and kidney graft deterioration by preventing the recovery from injury. Inhibiting premature senescence could have therapeutic benefit in kidney transplantation but has to be balanced against the risks of suspending antitumor defenses.

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.

Telomeres of most somatic cells progressively shorten, compromising the regenerative capacity of human tissues during aging and chronic diseases and after acute injury. Whether telomere shortening reduces renal regeneration after acute injury is unknown. Here, renal ischemia-reperfusion injury led to greater impairment of renal function and increased acute and chronic histopathologic damage in fourth-generation telomerase-deficient mice compared with both wild-type and first-generation telomerase-deficient mice. Critically short telomeres, increased expression of the cell-cycle inhibitor p21, and more apoptotic renal cells accompanied the pronounced damage in fourth-generation telomerase-deficient mice. These mice also demonstrated significantly reduced proliferative capacity in tubular, glomerular, and interstitial cells. These data suggest that critical telomere shortening in the kidney leads to increased senescence and apoptosis, thereby limiting regenerative capacity in response to injury.

Aortic pulse wave velocity (PWV), an indicator of arterial stiffness, independently predicts cardiovascular mortality risk in adults. Arterial stiffening advances with age and seems accelerated in children with certain disease conditions such as chronic kidney disease or diabetes. The Vicorder, an oscillometric device to measure PWV, has been validated in children, but reference values in a large pediatric cohort, association to carotid stiffness and influence of individual and family risk factors have not been determined. Pulse waves were captured in 1,003 healthy children (aged 6–18 years) in 6 centers and gender-specific reference data normalized to age/height were constructed. In 589 children carotid distensibility and intima media thickness were measured. Gestational and family history was reported. PWV correlated with age (r = 0.57, P < 0.0001) with significant gender-related differences starting at age 9. Further significant correlations were seen for height, weight, body mass index, blood pressure, pulse pressure, and heart rate. Independent predictors for PWV in a multivariate regression analysis were gender, age, height, weight, mean arterial pressure, and heart rate. Risk factors for higher PWV included small for gestational age at birth, secondhand smoking, parental hypertension, and obesity. PWV showed weak correlations with 2 of the carotid distensibility measures, but not with intima media thickness. This study defines reference values for PWV captured by the Vicorder device in children and adolescents and reveals associations with potential cardiovascular risk factors in a healthy population. Gender-specific percentiles for age/height will allow for the assessment of pediatric cohorts using this oscillometric method.