Background. The cellular infiltration and matrix accumulation accompanying
acute renal ischemia and reperfusion have been frequently noted but poorly
defined. The long-term consequences of ischemia may irreversibly damage the
kidney.
Methods. Female Sprague-Dawley rats (200 g) underwent unilateral nephrectom
y. After five days, the left renal pedicle was occluded for 45 minutes. Ani
mals were sacrificed at 0, 1, 2, 4, 8, 16, 32, 64, and 180 days postischemi
a (N = 6). Immunohistochemistry for monocytes/macrophages (Mo/M phi, ED-1),
myofibroblasts [alpha-smooth muscle actin (alpha-SMA)], collagen III and T
V, matrix metalloproteinase-2 (MMP-2) and proliferating cell nuclear antige
n (PCNA) and terminal dUTP nick end labeling (TUNEL) were performed.
Results. Kidney weights of postischemic animals were increased at all time
points (postischemic to controls, 1.47 +/- 0.21 to 0.94 +/- 0.12 g at day 8
; 1.49 +/- 0.20 to 1.27 +/- 0.13 g at day 64; and 1.86 +/- 0.1 to 1.24 +/-
0.2 g at day 180). Serum creatinine values increased to 0.42 +/- 0.10 mmol/
L at day 2 but returned to control levels by day 8 (0.05 mmol/L). Glomerula
r collagen IV was decreased from 2 to 16 days postischemia, which was accom
panied by an increase in MMP-2. The fractional area of the interstitium was
greatest at day 8 (19.55 +/- 0.91% compared with day 0 at 8.08 +/- 0.27%),
with a second increase observed at day 180 (16.61 +/- 0.70%). Interstitial
Mo/M phi increased postischemia from days 2 through 8 (8.84 +/- 2.12 to 13
3.32 +/- 14.04 per 0.91 mm(2)) and then decreased. Myofibroblasts prolifera
ted locally (PCNA double labeling was demonstrated), and increased numbers
were found from days 2 through 16 (maximal at day 8, 26.96 +/- 3.04%, compa
red with day 0, 0.88 +/- 0.11%). In the postischemic groups, collagen IV in
creased to day 8 (20.84 +/- 1.30%), but then decreased to below control val
ues at day 64 (2.22 +/- 0.15%) before returning to normal by day 180. Inter
stitial collagen III increased to 8 days (0.45 +/- 0.07% to 2.55 +/- 0.36%)
and then decreased to control levels by day 32, but showed a marked increa
se to approximately 6% at days 64 and 180. Cellular proliferation (PCNA) wa
s maximal at days 2 and 4 (affecting tubule cells and myofibroblasts but no
t macrophages). Apoptosis was maximal at day 8 (in both interstitial and tu
bule cells) in the postischemic groups.
Conclusion. Marked changes in the accumulation of Mo/M phi, MF, and collage
n IV were found in this model of ischemic acute renal failure. The reversib
ility of functional and structural changes is in marked contrast to that fo
und in progressive disease. The increases observed for collagen III at 64 a
nd 180 days postischemia suggest that in the long term, however, further ch
ronic structural changes may be observed.