Increased susceptibility of aging kidney to ischemic injury: identification of candidate genes changed during aging, but corrected by caloric restriction

Abstract

Aging is associated with an increased incidence and severity of acute renal failure. However, the molecular mechanism underlying the increased susceptibility to injury remains undefined. These experiments were designed to investigate the influence of age on the response of the kidney to ischemic injury and to identify candidate genes that may mediate this response. Renal slices prepared from young (5 mo), aged ad libitum (aged-AL; 24 mo), and aged caloric-restricted (aged-CR; 24 mo) male Fischer 344 rats were subjected to ischemic stress (100% N2) for 0 -60 min. As assessed by biochemical and histological evaluation, slices from aged-AL rats were more susceptible to injury than young counterparts. Importantly, caloric restriction attenuated the increased susceptibility to injury. In an attempt to identify the molecular pathway(s) underlying this response, microarray analysis was performed on tissue harvested from the same animals used for the viability experiments. RNA was isolated and the corresponding cDNA was hybridized to CodeLink Rat Whole Genome Bioarray slides. Subsequent gene expression analysis was performed using GeneSpring software. Using two-sample t-tests and a twofold cut-off, the expression of 92 genes was changed during aging and attenuated by caloric restriction, including claudin-7, kidney injury molecule-1 (Kim-1), and matrix metalloproteinase-7 (MMP-7). Claudin-7 gene expression peaked at 18 mo; however, increased protein expression in certain tubular epithelial cells was seen at 24 mo. Kim-1 gene expression was not elevated at 8 or 12 mo but was at 18 and 24 mo. However, changes in Kim-1 protein expression were only seen at 24 mo and corresponded to increased urinary levels. Importantly, these changes were attenuated by caloric restriction. MMP-7 gene expression was decreased at 8 mo, but an age-dependent increase was seen at 24 mo. Increased MMP-7 protein expression in tubular epithelial cells at 24 mo was correlated with the gene expression pattern. In summary, we identified genes changed by aging and changes attenuated by caloric restriction. This will facilitate investigation into the molecular mechanism mediating the age-related increase in susceptibility to injury. ischemia; microarray analysis ISCHEMIA IS A LEADING cause of acute renal failure (ARF), which develops in ϳ4 -7% of hospitalized patients each year (20).Common conditions leading to ischemia include cardiovascular disease, stroke, dehydration, and surgery, all of which place the elderly population at risk for ischemic ARF. Although the mortality rates for ARF are decreasing, the rates still range from 20 to 35% (45, 47). Importantly, Xue et al. (47) established age as a risk factor for ARF. This is in agreement with previous studies that have associated age with a higher risk for ARF (25,29,30). Pascual et al. (26) suggested that the incidence of ARF is 3.5 times higher in patients over 70 and the aged patients had a higher mortality rate. However, little is known about the molecular mechanism(s) that underlie the age-depen...

The impact of aging on kidney repair

“…This has been observed in humans with AKI (65,104) and has been corroborated in rodent studies of renal ischemia-reperfusion (I/R) which demonstrate significantly greater injury in older animals (71,78,81,106). Mechanisms that are thought to contribute to this higher susceptibility include structural and functional changes in the renal vascular system leading to diminished perfusion (78) and a lower epithelial stress resistance that has been ascribed to an accelerated rate of ATP depletion due to mitochondrial alterations (1,14,58,84). It has also been proposed that parenchymal loss in the aging kidney directly confers a higher susceptibility to acute damage, although this is not supported by experimental data in which the reduction of renal mass surprisingly protected against I/R injury in a rat model of 5/6 nephrectomy (100).…”

“…It has also been proposed that parenchymal loss in the aging kidney directly confers a higher susceptibility to acute damage, although this is not supported by experimental data in which the reduction of renal mass surprisingly protected against I/R injury in a rat model of 5/6 nephrectomy (100). As we gain more mechanistic insight into the complex events that occur during aging, it is clear that many of these changes not only increase the susceptibility to acute damage but also impact the repair phase after injury (14,81).…”

Structural Equation Modeling Highlights the Potential of Kim-1 as a Biomarker for Chronic Kidney Disease

“…Male Fischer 344 rats were fed an ad libitum (AL) diet; this is an established model of chronic renal dysfunction [13] that has been used by our laboratory [14,15]. Importantly, age-dependent alterations in renal structure and function can be attenuated by lifelong caloric restriction (CR) [16]; this adds an additional control for this model.…”

Zag Expression during Aging Suppresses Proliferation after Kidney Injury

“…1 Aging is thought to increase the susceptibility to AKI 2-5 as a result of functional changes in the vasoregulatory reserve 4,6 and a loss of cellular stress resistance. 7 The age-dependent increase in the susceptibility to AKI coincides with a decline in functional renal recovery. According to our recent meta-analysis, 8 it is estimated that patients who are older than 65 yr carry a 28% higher risk for failing to recover renal function completely after surviving an episode of AKI.…”