LOCAL MACROPHAGE AND MYOFIBROBLAST PROLIFERATION IN PROGRESSIVE RENALINJURY IN THE RAT REMNANT KIDNEY

Background. We have recently shown that blockade of angiotensin II act ivity inhibits local macrophage and myofibroblast proliferation in pro gressive non-immune renal injury in the rat remnant kidney. However, i t is not known whether this local proliferation contributes to macroph age 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 operat ion. Macrophage and myofibroblast proliferation was assessed by two-co lour immunostaining for ED1(+) macrophages or alpha-smooth muscle acti n (alpha-SMA)-positive myofibroblasts with the proliferating cell nucl ear antigen (PCNA) or bromodeoxyuridine. Results. All parameters of re nal function and histology remained normal in the sham-operated contro ls, and no macrophage or myofibroblast accumulation was evident. In co ntrast, prominent macrophage accumulation developed in both the glomer ulus and tubulointerstitium in STNx animals, peaking at week 12. Many ED1(+) macrophages showed PCNA expression, accounting for 19-34% of th e total macrophage population. There was a highly significant correlat ion between proliferating macrophages and total macrophage accumulatio n in the glomerulus (r=0.82, P<0.0001) and tubulointerstitium (r=0.70, P<0.001). Macrophage proliferation was largely restricted to focal ar eas of renal damage, such as glomerular segmental lesions and severe t ubulointerstitial damage. Also, the subpopulation of proliferating mac rophages gave a highly significant correlation with loss of renal func tion, proteinuria, and glomerular and tubulointerstitial lesions. In a ddition, many alpha-SMA myofibroblasts were evident within expanded me sangial areas and the tubulointerstitium following STNx. Interestingly , active lesions contained many large alpha-SMA(+) cells double-staine d for PCNA, accounting for 24-29% of total myofibroblasts. There was a highly significant correlation between the number of proliferating my ofibroblasts and total myofibroblast accumulation during the evolution of this disease, and both populations correlated with progressive ren al injury. Conclusions. This study has shown that local proliferation is an important mechanism in both macrophage and myofibroblast accumul ation during the development of renal injury in the rat remnant kidney . In addition, local macrophage proliferation is postulated as a mecha nism for amplifying kidney damage in non-immune renal injury.