Local macrophage and myofibroblast proliferation in progressive renal injury in the rat remnant kidney

Background. We have recently shown that blockade ofangiotensin II activity inhibits local macrophage and myofibroblastproliferation in progressive non-immune renal injury in the rat remnantkidney. However, it is not known whether this local proliferationcontributes to macrophages and myofibroblast accumulation and thedevelopment of renal injury. Therefore, we examined this issue in adetailed time-course study of the rat remnant kidney.Methods. Groups of five rats were killed 4, 8, 12 or16 weeks after 5/6 subtotal nephrectomy (STNx) or a sham operation.Macrophage and myofibroblast proliferation was assessed by two-colourimmunostaining for ED1⁺ macrophages or&agr;-smooth muscle actin (&agr;-SMA)-positive myofibroblasts withthe proliferating cell nuclear antigen (PCNA) or bromodeoxyuridine.Results. All parameters of renal function andhistology remained normal in the sham operated controls, and no macrophageor myofibroblast accumulation was evident. In contrast, prominentmacrophage accumulation developed in both the glomerulus andtubulointerstitium in STNx animals, peaking at week 12. ManyED1⁺ macrophages showed PCNA expression, accountingfor 19-34% of the total macrophage population. There was a highlysignificant correlation between proliferating macrophages and totalmacrophage 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 renaldamage, such as glomerular segmental lesions and severe tubulointerstitialdamage. Also, the subpopulation of proliferating macrophages gave a highlysignificant correlation with loss of renal function, proteinuria, andglomerular and tubulointerstitial lesions. In addition, many &agr;-SMAmyofibroblasts were evident within expanded mesangial areas and thetubulointerstitium following STNx. Interestingly, active lesions containedmany large &agr;-SMA⁺ cells double-stained forPCNA, accounting for 24-29% of total myofibroblasts. There was a highlysignificant correlation between the number of proliferating myofibroblastsand total myofibroblast accumulation during the evolution of this disease,and both populations correlated with progressive renal injury.Conclusions. This study has shown that localproliferation is an important mechanism in both macrophage andmyofibroblast accumulation during the development of renal injury in therat remnant kidney. In addition, local macrophage proliferation ispostulated as a mechanism for amplifying kidney damage in non-immune renalinjury.