Functional versus structural changes in the pathophysiology of acute ischemic renal failure in aging rats

Abstract

The aim of this study was to gain further insight into the greater susceptibility to acute ischemic renal failure (ARF, 30 min of renal arteries clamping) of old rats (O, 18 months) as against young rats (Y, 3 months). All the rats ate a hypoproteic diet (14% of casein) to avoid age-related glomerulosclerosis in O. Basal renal dynamics was similar in O and Y (Groups CON). One day after ARF, the decrease in GFR was more severe in O than in Y (-82% and -57% vs. respective CON, P < 0.05), due to a greater rise of RVR in O (+258%) than in Y (+104%). The histological renal damage after ischemia was comparable in the two groups with ARF. Five days after ARF, the recovery of renal function was characterized by a slower rise of GFR in O than in Y. In two further groups, two different scavengers of oxygen-free radicals, dimethylthiourea (DMTU) and superoxide dismutase (SOD), were administered at the time of arterial occlusion. DMTU had protective effects in Y but not in O (delta GFR was -28% and -72%, respectively); in contrast, SOD was more effective in O (delta GFR = -58%) than in Y rats (delta GFR = -40%). To test the hypothesis that such a difference was related to the capacity of SOD to increase the levels of nitric oxide (NO), four more groups of Y and O rats were pretreated with L-arginine (ARG), precursor of NO, in tap water (1.5%). No difference in renal dynamics was detected in basal conditions.(ABSTRACT TRUNCATED AT 250 WORDS)

Atorvastatin Improves the Course of Ischemic Acute Renal Failure in Aging Rats

“…Both Y and O rats were fed a moderately hypoproteic diet from birth (protein content, 14% as casein); previous studies in this laboratory have shown that such a diet delays the occurrence of age-related glomerulosclerosis while permitting a normal growth (3). After arriving at our facility, the rats were administered either the standard diet or a diet supplemented with ATO with free access to tap water for at least 14 d. The amount of ATO in the diet was calculated according to daily food intake of the rats to deliver about 15 mg/kg/d in Y rats and 12 mg/kg/d in O rats.…”

“…A previous study from our laboratory has shown that ischemic injury after renal arteries clamping determines a more pronounced decrease of renal plasma flow (RPF) and GFR in old (O) rats when compared with young (Y) rats (3). Renal impairment in aging rats, however, was partially blunted by the administration of oral supplements of either arginine, the precursor of nitric oxide (NO), or SOD, a scavenger of reactive oxygen species (ROS), clearly suggesting that an endothelial dysfunction, secondary to NO deficiency and increased ROS production, was the main factor responsible for the intense renal vasoconstriction of aging animals (3).…”

“…A previous study from our laboratory has shown that ischemic injury after renal arteries clamping determines a more pronounced decrease of renal plasma flow (RPF) and GFR in old (O) rats when compared with young (Y) rats (3). Renal impairment in aging rats, however, was partially blunted by the administration of oral supplements of either arginine, the precursor of nitric oxide (NO), or SOD, a scavenger of reactive oxygen species (ROS), clearly suggesting that an endothelial dysfunction, secondary to NO deficiency and increased ROS production, was the main factor responsible for the intense renal vasoconstriction of aging animals (3). Although that study raised the theoretical possibility that some unfavorable effects due to renal hypoperfusion in the elderly could be prevented, to date, there is no definitive evidence that a specific prophylactic treatment can reduce the occurrence of these events in aging, because the use of arginine as precursor of NO does not seem to be indicated in the elderly on the basis of the better knowledge of the metabolism of this amino acid and its possible side effects after oral administration (4).…”

“…On this basis, we have hypothesized that statins could play a role in preventing the susceptibility to ischemic damage of aging rats, given the ability of these drugs to increase NO synthesis (6) and to reduce both inflammation (7) and ROS production (8), factors involved in the pathogenesis of the endothelial dysfunction of the elderly (3,9). Therefore, the aim of the study presented here was to investigate whether the prolonged treatment with low doses of atorvastatin (ATO) could improve the course of ARF after ischemia-reperfusion injury in aging rats compared with untreated age-matched rats.…”

“…Therefore, the aim of the study presented here was to investigate whether the prolonged treatment with low doses of atorvastatin (ATO) could improve the course of ARF after ischemia-reperfusion injury in aging rats compared with untreated age-matched rats. To exclude the notion that the morphologic changes of aging (glomerular sclerosis, tubular atrophy, and arteriolosclerosis) (1) would have conditioned the degree of postischemic damage, only O rats without agerelated nephropathy were used in this study (3). Because the positive effects of statins in endothelial protection seem to be mediated in vitro by the changes in the activity of the small G-proteins (Ras and Rho) and by the increased expression of endothelial NO synthase (eNOS) (10), we have also evaluated the modifications induced by ATO treatment on these proteins in the aging rat, a model in which these systems have never been investigated.…”