Nephrology Dialysis Transplantation, Vol 13, Issue 9 2216-2226, Copyright © 1998 by Oxford University Press
G Thomas, B Yang, B Wagner, J Savill and A El Nahas
Background: The progression of chronic renal failure
(CRF) is associated with the progressive deletion of renal cells along with
the fibrosis of the kidney. We have studied the role of programmed cell
death (apoptosis) in the progression of experimental CRF and renal
scarring. Methods: The sub-total (5/6th) nephrectomy
(SNx) model of CRF was studied in adult male Wistar rats, with renal tissue
collected from experimental and control animals on days 7, 15, 30, 60, 90,
and 120 post SNx (n-6 per group). These were examined for morphological
signs of apoptosis by light and electron microscopy. Further, we stained
the nuclear chromatin by the acridine orange fluorescent method and
detected signs of DNA cleavage by endonucleases via the principal of TUNEL
staining (ApopTag™). Rates of cellular proliferation were
measured simultaneously by immunohistochemical staining for the
proliferating cell nuclear antigen (PCNA). In addition, cell division was
monitored by counting of morphologically mitotic motifs detectable by light
microscopy. Results: Progressive renal insufficiency
associated with glomerulosclerosis and tubulointerstitial fibrosis took
place in the majority of SNx rats. In these animals, we noted a marked and
progressive increase in the number of apoptotic glomerular, tubular as well
as interstitial cells. The most significant apoptotic changes were seen in
the tubules of remnant kidneys peaking at day 120 post-SNx. At this stage,
the increase in apoptosis compared to controls was 10.33±2.67
(M±SEM) fold for glomerular cells (P⩽0.006),
26.20±4.56 fold for tubular cells (P<0.0001) and
4.66±0.81 fold for interstitial cells (P⩽0.01). Parallel
changes in the number of PSNA positive renal cells were observed. Maximal
PCNA staining was seen at day 120 when the increase with respect to
controls was 14.00±4.93 fold (P⩽0.05) for glomerular
cells, 60.01±12.20 fold (P⩽0.05) for tubular cells and
28.59±4.45 fold ((P⩽0.05) for interstitial cells. As
expected the number of cells undergoing division and detectable by
conventional light microscopy was lower at any time point to those
expressing PCNA. We also observed a close correlation between the severity
of tubular atrophy and tubulointerstitial fibrosis with the rate of tubular
apoptosis (r=0.970, R2=0.941, P⩽0.001).
Conclusions: We have shown a time-dependent increase
in apoptosis and PCNA antigen positive staining in the sub-total
nephrectomy model of chronic renal failure correlating with the progression
of renal fibrosis. PCNA staining did not match analysis for mitosis and was
considered to overestimate the number or proliferating cells in the tissue.
With this reservation in mind and taking into account the relative
time-frames in vivo of apoptosis and proliferation;
apoptosis potentially outweighs proliferation by a factor of 2-8-fold, when
examined over the same time period. Consequently, even small changes in the
finite numbers of apoptotic cells become highly significant. Our results
have shown the definite role of apoptosis within progression of renal
damage and highlighted how it may contribute to the progression of tubular
atrophy and play a role in the pathogenesis of tubulo-interstitial
scarring. Key words: apoptosis; subtotal nephrectomy;
cellular proliferation; glomerulosclerosis; tubulointerstitial fibrosis;
chronic renal failure
ORIGINAL ARTICLES
Cellular apoptosis and proliferation in experimental renal fibrosis
Sheffield Kidney Institute and Department of Histopathology, Northern General Hospital Trust, Herries Road, Sheffield, S5 7AU, UK; Division of Renal and Inflammatory Disease, Department of Medicine, University Hospital, Nottingham, UK
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