Lower antioxidant capacity and elevated p53 and p21 may be a link between gender disparity in renal telomere shortening, albuminuria, and longevity

Abstract

It is well documented that females live longer than males and more renal damage occurs in males. However, the underlying mechanisms are not fully understood. The aim of this study was to define aging effects on albuminuria and kidney telomere length from male and female rats and to determine mechanisms, which may explain any observed differences. Cellular senescence is known to play a major role in nephropathology, and as such, a range of senescence markers were compared in male and female renal tissue. Oxidative stress has been shown to accelerate telomere shortening and elicit cellular growth arrest. Thus major antioxidants, MnSOD, glutathione peroxidase I, and glutathione reductase, were also evaluated. Urinary albumin excretion increased with age in both sexes, but the increase was greater in males than females. In the cortex and medulla of both male and female rats, age-related telomere shortening occurred, the effect being more pronounced in males than in females. The cortical region had more short telomeres than the medulla in both genders. p53 And p21 expression over time significantly increased in males, but not in females. MnSOD expression was elevated in female vs. male cortex. Gxp1 and glutathione reductase levels were increased in the older female cortex compared with males. Our findings indicate that a reduction in oxidative damage protection may be responsible for accelerated telomere shortening over time, resulting in increased cellular senescence, loss of renal function, and death in male rats.

Metabolism of a Heterocyclic Amine Colon Carcinogen in Young and Old Rats

“…Renal telomere shortening, due in part to free radical damage, and an increase in cell senescence markers have been observed in the old kidney (Tarry-Adkins et al, 2006). Of direct relevance to the present study is the fact that there is an increase in DNA adducts (8-hydroxy-2Ј-deoxyguanosine) in the F344 rat kidney with age (Hamilton et al, 2001).…”

Sex differences in developmental programming models

“…It is known that telomere length in both the renal cortex and the medulla of male rats is shorter than in females and that telomere shortening is associated with increased markers of cellular senescence (Tarry-Adkins et al 2006). In male rats, it has also been shown that prenatal exposure to a maternal low-protein diet in rats shortens telomeres prematurely in a number of organs (Tarry-Adkins et al 2008), but the effect is less well studied in females.…”

The Clinical Importance of Nephron Mass

“…98,99,154 -156 Evidence from rodents demonstrated an accelerated senescence in kidneys, hearts, and aortas and premature mortality in LBW offspring experiencing rapid catch-up growth. [157][158][159][160] This has not been rigorously studied in humans. Leukocyte telomere lengths are not different between SGA and AGA infants at birth, but telomeres are shorter in SGA children at 5 years, suggesting programmed accelerated senescence, likely as a consequence of catch-up growth and increased oxidative stress, may also contribute to developmental programming of adult disease.…”