Changes With Age in the Renal Function in Adult Men

Lewis, William H.; Alving, Alf S.

doi:10.1152/ajplegacy.1938.123.2.500

Cited by 122 publications

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“…At 23 months of age, rats were assigned randomly to drug treatment with the ET A [3] 54 [4] 56 [6] 54 [7] Hematocrit (%) 47 [3] 46 [2] 48 [3] 48 [1] Distribution volume is expressed in absolute values for exogenous creatinine (mL) as fraction of body volume (grams of body weight in mL Figure 3b), and reversed podocyte injury and glomerular basement membrane hypertrophy (Figure 2c and 2d). In aged rats, treatment had no effect on tubulo-interstitial injury (injury score 1.…”

Section: Resultsmentioning

confidence: 99%

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Role of Podocytes for Reversal of Glomerulosclerosis and Proteinuria in the Aging Kidney After Endothelin Inhibition

et al. 2004

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Abstract-The cause of focal-segmental glomerulosclerosis as a consequence of physiological aging, which is believed to be inexorable, is unknown. This study investigated whether inhibition of endothelin-1, a growth-promoting peptide contributing to renal injury in hypertension and diabetes, affects established glomerulosclerosis and proteinuria in the aged kidney. We also determined the role of endothelin receptors for podocyte injury in vivo and in vitro. Aged Wistar rats, a model of spontaneous age-dependent glomerulosclerosis, were treated with the orally active endothelin subtype A (ET A ) receptor antagonist darusentan, and evaluation of renal histology, renal function studies, and expression analyses were performed. In vitro experiments using puromycin aminonucleoside to induce podocyte injury investigated the role of ET A receptor signaling for apoptosis, cytoskeletal injury, and DNA synthesis. In aged Wistar rats, established glomerulosclerosis and proteinuria were reduced by Ͼ50% after 4 weeks of darusentan treatment, whereas blood pressure, glomerular filtration rate, or tubulo-interstitial renal injury remained unaffected. Improvement of structural injury in glomeruli and podocytes was accompanied by a reduction of the expression of matrix metalloproteinase-9 and p21 Cip1/WAF1 . In vitro experiments blocking ET A receptors using specific antagonists or RNA interference prevented apoptosis and structural damage to podocytes induced by puromycin aminonucleoside. In conclusion, these results support the hypothesis that endogenous endothelin contributes to glomerulosclerosis and proteinuria in the aging kidney. The results further suggest that age-dependent glomerulosclerosis is not merely a "degenerative" but a reversible process locally confined to the glomerulus involving recovery of podocytes from previous injury. Key Words: arterial presure Ⅲ nephrosclerosis Ⅲ DNA Ⅲ kidney failure Ⅲ renal artery Ⅲ expression Ⅲ kidney Ⅲ renal disease A ging represents an important factor determining onset and course of disease and has become a significant issue in view of the anticipated increase of the aging population. Aging in humans and rodents progressively impairs renal function 1,2 and structure, the latter of which is characterized by damage of podocytes and mesangial matrix, as well as capillary hypertrophy and obliteration resulting in glomerulosclerosis. 2 The exact mechanisms underlying agedependent renal injury are unknown. In otherwise healthy individuals Ն65 years of age, even in the absence of known risk factors such as hypertension or diabetes, glomerulosclerosis is frequently present. 3 Currently, Ϸ1.4% of the US total population is affected, and the incidence is expected to increase to Ͼ2% within the next 15 years. 3 Glomerulosclerosis and proteinuria involve injury of podocytes, also known as glomerular epithelial cells that maintain an intact filtration barrier and control glomerular basement membrane turnover under normal conditions. 4 -7 In addition to cell-specific changes during aging, cell c...

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Section: Resultsmentioning

confidence: 99%

“…Aging in humans and rodents progressively impairs renal function 1,2 and structure, the latter of which is characterized by damage of podocytes and mesangial matrix, as well as capillary hypertrophy and obliteration resulting in glomerulosclerosis. 2 The exact mechanisms underlying agedependent renal injury are unknown.…”

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confidence: 99%

Role of Podocytes for Reversal of Glomerulosclerosis and Proteinuria in the Aging Kidney After Endothelin Inhibition

et al. 2004

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“…Its terminal half-life was previously thought to be about 2 h, but recent studies have shown it to range from 27-693 h and nephrotoxicity is associated with abnormal tissue accumulation of the drug (Schentag et al, 1978a). It is also important to take into account the effects of age on renal function (Lewis & Alving, 1938;Davies & Shock, 1950;Rowe etal., 1976).…”

Section: Factors Influencing Nephrotoxicitymentioning

confidence: 99%

Assessment of nephrotoxicity.

Prescott¹

1982

Brit J Clinical Pharma

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“…Yet dehydration is a major health risk for the elderly (5), and the elderly are susceptible to dehydration because of increased fluid losses (41). Aged kidneys have a decreased ability to concentrate urine (17,27) and to conserve sodium (8), along with a relative resistance to vasopressin (25), and release less renin when challenged (6). These changes with age predispose the elderly to hypovolemia and dehydration because of the reduced ability to conserve water and sodium during times of relative water and sodium loss.…”

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Thirst and salt appetite responses in young and old Brown Norway rats

Thunhorst

Johnson²

2003

American Journal of Physiology-Regulatory, Integrative and Comp

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Thunhorst, Robert L., and Alan Kim Johnson. Thirst and salt appetite responses in young and old Brown Norway rats. Am J Physiol Regul Integr Comp Physiol 284: R317-R327, 2003. First published October 10, 2002 10.1152/ ajpregu.00368.2002 Norway rats aged 4 mo (young) and 20 mo (old) received a series of experimental challenges to body fluid homeostasis over ϳ3 mo. Water was available for drinking in some tests, and both water and 0.3 M NaCl were available in others. The series included three episodes of extracellular fluid depletion (i.e., furosemide ϩ 20 h of sodium restriction), two tests involving intracellular fluid depletion (i.e., hypertonic saline: 1 or 2 M NaCl at 2 ml/kg body wt sc), one test involving overnight food and fluid restriction, and testing with captopril adulteration of the drinking water (0.1 mg/ml) for several days. Old rats were significantly heavier than young rats throughout testing. Old rats drank less water and 0.3 M NaCl after sodium deprivation than young rats, in terms of absolute and body weightadjusted intakes. Old rats drank only half as much water as young rats in response to subcutaneous hypertonic NaCl when intakes were adjusted for body weight. Old rats drank less 0.3 M NaCl than young rats after overnight food and fluid restriction when intakes were adjusted for body weight. In response to captopril adulteration of the drinking water, young rats significantly increased daily ingestion of 0.3 M NaCl when it was available as an alternative to water and significantly increased daily water intakes when only water was available, in terms of absolute and body weight-adjusted intakes. Old rats had no response to captopril treatment. These results add important new information to previous reports that aging rats have diminished thirst and nearabsent salt appetite responses to regulatory challenges. aging; drinking; diuresis; natriuresis; dehydration; hypovolemia ELDERLY HUMANS CONSUME ADEQUATE fluids on a daily basis (7). Yet dehydration is a major health risk for the elderly (5), and the elderly are susceptible to dehydration because of increased fluid losses (41). Aged kidneys have a decreased ability to concentrate urine (17, 27) and to conserve sodium (8), along with a relative resistance to vasopressin (25), and release less renin when challenged (6). These changes with age predispose the elderly to hypovolemia and dehydration because of the reduced ability to conserve water and sodium during times of relative water and sodium loss. The elderly have decreased thirst sensation (24, 26, 32). As a result, they are slower than young people to restore fluid balance after exercise-induced dehydration (19) and water deprivation (26). It thus appears that the elderly are more vulnerable to the consequences of physiological challenges to body fluid homeostasis and that diminished thirst in the elderly contributes to their problems of fluid balance (15).The capacities of the aging kidney have been extensively investigated in rat models of aging. As in elderly humans, kidneys of aging r...

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Changes With Age in the Renal Function in Adult Men

Cited by 122 publications

References 0 publications

Role of Podocytes for Reversal of Glomerulosclerosis and Proteinuria in the Aging Kidney After Endothelin Inhibition

Role of Podocytes for Reversal of Glomerulosclerosis and Proteinuria in the Aging Kidney After Endothelin Inhibition

Assessment of nephrotoxicity.

Thirst and salt appetite responses in young and old Brown Norway rats

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