Nephrology Dialysis Transplantation, Vol 13, Issue 10 2509-2518, Copyright © 1998 by Oxford University Press
N Gassler, M Elger, D Inoue, W Kriz and M Amling
Background. A main function attributed to B cell
leukaemia/lymphoma 2 gene (bcl-2) is its ability to confer resistance
against apoptosis. In bcl-2 deficient mice, extensive apoptosis occurs
during abnormal nephrogenesis, and renal failure is found very quickly
after birth. However, the underlying mechanisms remain poorly understood.
The aim of the present study was to clarify whether the degenerative
process in the kidneys seen after birth is based either on increased
apoptosis of glomerular cells or on mechanisms independent from the genetic
defect. Materials and methods. Kidneys from
7-56-day-old bcl-2 knockout mice and wild-type litter mates were studied.
Glomerula number, glomerular tuft volume, cell counts in 'non-sclerotic'
glomeruli as well as the glomerular damage score were determined by
histomorphometrical studies. Apoptosis was evaluated by morphological
criteria and the terminal deoxynucleotidyl transferase-mediated dUTP nick
end-labelling (TUNEL)-technique. Results.
The number of nephrons at birth was severely decreased in bcl-2
knockout mice compared to controls (<20%;
P<0.001). These nephrons undergo dramatic
hypertrophy with an approximately 4-fold increase in volume
(P<0.001). In hypertrophic, but 'non-sclerotic'
glomeruli, the number density of glomerular cells progressively declined
with time (P<0.001). Starting with day 20,
enlarged glomeruli developed sclerosis beginning with a segmental
distribution, but quickly progressing to global sclerosis. Apoptosis was
neither detected in non-sclerotic glomeruli nor in stages prior to fully
established sclerosis. As shown by the glomerular damage score, post-natal
degeneration of kidneys from bcl-2 knockout animals proceeded rapidly.
Conclusions. Bcl-2 knockout mice exhibit deficient
nephrogenesis resulting in severe oligonephronia at birth. Post-partum
development of glomerulosclerosis does not seem to be due to augmented
apoptosis. The degenerative process appears to be based on a glomerular
overload with increased mechanical stress to the filtration barrier,
leading via glomerula hypertrophy, podocyte damage and formation of tuft
adhesions to glomerulosclerosis. Keywords: bcl-2;
glomerulosclerosis; pathology
ORIGINAL ARTICLES
Oligonephronia, not exuberant apoptosis, accounts for the development of glomerulosclerosis in the bcl-2 knockout mouse
Institut fur Anatomie und Zellbiologie I, Universitat Heidelberg, Heidelberg, Germany; Departments of Cell Biology and Orthopaedics, Yale University School of Medicine, New Haven, CT, USA; Division of Endocrinology, First Department Internal Medicine, Tokushima University, Tokushima, Japan; Abteilung fur Unfall- und Wiederherstellungschiurgie, Universitat Hamburg, Hamburg, Germany; Corresponding author address: Pathologisches Institut, Im Neuenheimer Feld 220/221, D-69120 Heidelberg, Germany
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