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 macrophage 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 alpha-smooth muscle actin (alpha-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 alpha-SMA myofibroblasts were evident within expanded mesangial areas and the tubulointerstitium following STNx. Interestingly, active lesions contained many large alpha-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 nonimmune renal injury.
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 macrophage 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 alpha-smooth muscle actin (alpha-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 alpha-SMA myofibroblasts were evident within expanded mesangial areas and the tubulointerstitium following STNx. Interestingly, active lesions contained many large alpha-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 nonimmune renal injury.
Authors: Jin H Li; Wansheng Wang; Xiao R Huang; Matthew Oldfield; Ann M Schmidt; Mark E Cooper; Hui Y Lan Journal: Am J Pathol Date: 2004-04 Impact factor: 4.307
Authors: Sony Prasad; John Patrick McDaid; Frederick Wai Keung Tam; John Lionel Haylor; Albert Chee Meng Ong Journal: Am J Pathol Date: 2009-09-03 Impact factor: 4.307