Nephrology Dialysis Transplantation, Vol 13, Issue 8 1967-1974, Copyright © 1998 by Oxford University Press
N Yang, L Wu, D Nikolic-Paterson, Y Ng, W Yang, W Mu, R Gilbert, M Cooper, R Atkins and H Lan
Background. We have recently shown that blockade of
angiotensin II activity inhibits local macrophage and myofibroblast
proliferation in progressive non-immune renal injury in the rat remnant
kidney. However, it is not known whether this local proliferation
contributes to macrophages and myofibroblast accumulation and the
development of renal injury. Therefore, we examined this issue in a
detailed time-course study of the rat remnant kidney.
Methods. Groups of five rats were killed 4, 8, 12 or
16 weeks after 5/6 subtotal nephrectomy (STNx) or a sham operation.
Macrophage and myofibroblast proliferation was assessed by two-colour
immunostaining for ED1+ macrophages or
&agr;-smooth muscle actin (&agr;-SMA)-positive myofibroblasts with
the proliferating cell nuclear antigen (PCNA) or bromodeoxyuridine.
Results. All parameters of renal function and
histology remained normal in the sham operated controls, and no macrophage
or myofibroblast accumulation was evident. In contrast, prominent
macrophage accumulation developed in both the glomerulus and
tubulointerstitium in STNx animals, peaking at week 12. Many
ED1+ macrophages showed PCNA expression, accounting
for 19-34% of the total macrophage population. There was a highly
significant correlation between proliferating macrophages and total
macrophage accumulation in the glomerulus (r = 0.82,
P <0.0001) and tubulointerstitium
(r = 0.70, P <0.001).
Macrophage proliferation was largely restricted to focal areas of renal
damage, such as glomerular segmental lesions and severe tubulointerstitial
damage. Also, the subpopulation of proliferating macrophages gave a highly
significant correlation with loss of renal function, proteinuria, and
glomerular and tubulointerstitial lesions. In addition, many &agr;-SMA
myofibroblasts were evident within expanded mesangial areas and the
tubulointerstitium following STNx. Interestingly, active lesions contained
many large &agr;-SMA+ cells double-stained for
PCNA, accounting for 24-29% of total myofibroblasts. There was a highly
significant correlation between the number of proliferating myofibroblasts
and total myofibroblast accumulation during the evolution of this disease,
and both populations correlated with progressive renal injury.
Conclusions. This study has shown that local
proliferation is an important mechanism in both macrophage and
myofibroblast accumulation during the development of renal injury in the
rat remnant kidney. In addition, local macrophage proliferation is
postulated as a mechanism for amplifying kidney damage in non-immune renal
injury. Keywords: macrophage; myofibroblast;
proliferation; fibrosis; &agr;-smooth muscle actin; renal injury
ORIGINAL ARTICLES
Local macrophage and myofibroblast proliferation in progressive renal injury in the rat remnant kidney
Department of Nephrology, Monash Medical Centre and Department of Medicine, Austin and Repatriation Medical Centre, Victoria, Australia; Department of Nephrology, First Affiliated Hospital of Sun Yat-Sen University of Medical Sciences, Guangzhou, China; Veterans General Hospital, Yang-Ming University, Taiwan; Correspondence to: HY Lan, Department of Nephrology, Monash Medical Center, Clayton Road, Clayton, Victoria, Australia 3168
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