Abstract
Aim: To determine the time-course of collecting duct (CD) ectasia, proliferation
and the expression of G1-phase cyclin partners of cyclin-dependent kinases
(Cdks) 2 and 4, in a model of autosomal recessive polycystic kidney disease
(ARPKD).
Introduction: In ARPKD, cyst formation arises from the synchronized and fusiform
dilatation of CD and distal nephron tubules. Here, we investigated the
hypothesis that proliferation and cell cycle activation in CD epithelial cells
occurs during the early but not the late phase of ARPKD.
Methods: Kidneys from Lewis polycystic kidney disease (LPK) rats (an ARPKD
model) were examined at postnatal weeks (wk) 1, 3, 6, 12, 16 and 24 and
compared to control animals.
Results: Kidney maturation (as shown by the persistence of comma-shaped
bodies) was delayed in LPK rats at wk1. The physiological distribution of Ki-67
and cyclin D1 in medullary rays was preserved but focal areas of dilated CDs were
detected in LPK rats, and epithelial cells expressed Ki-67, cyclin D1 and E. By wk
3, CD ectasia was diffuse in the outer medulla and cortex, and from wk 6 was
associated with interstitial fibrosis. The mean luminal diameter of CDs increased
from wks 1 to 24 (wk1: 1.16 1 0.24; wk3: 5.66 1 1.03; wk6: 5.55 1 0.82; wk16:
8.17 1 1.39; wk s24: 15.65 1 4.04 arbitrary units; P < 0.05). The proliferation
index (Ki-67-positive cells) of CDs peaked between wks 3 to 6 in the cortex and
outer medulla, falling to control levels by wk 24. Similarly the number of cyclin
D1-positive CDs peaked at wks 3 to 6, whereas the number of cyclin E-positive
CDs increased progressively, peaking at wk 24.
Conclusion: These data suggest that anti-proliferative therapies are likely to be
most effective in reducing CD ectasia if commenced early (before week 6) in this
model. The sustained increase in cyclin E also indicates that Cdk2 may have a
pathological role, independent of proliferation.
Original language | English |
---|---|
Article number | 074 |
Pages (from-to) | A118-A118 |
Number of pages | 1 |
Journal | Nephrology |
Volume | 13 |
Issue number | Supplement s3 |
Publication status | Published - Sept 2008 |
Externally published | Yes |
Event | 44 Annual Scientific Meeting of the Australian and New Zealand Society of Nephrology - Newcatle, Australia Duration: 6 Sept 2008 → 10 Sept 2008 |