Impaired angiogenesis in the remnant kidney model: I. Potential role of vascular endothelial growth factor and thrombospondin-1

Few studies have examined the role of the microvasculature in progressive r enal disease. It was hypothesized that impaired angiogenesis might occur in the diseased kidney and could contribute to renal scarring. Progressive re nal disease was induced in rats by 5/6 renal ablation and those rats were c ompared with sham-operated control animals at multiple time points, for exa mination of changes in the microvasculature and the expression of angiogeni c factors. An early angiogenic response was documented in remnant kidneys, with increases in the proliferation of peritubular (1 wk) and glomerular (2 wk) endothelial cells. Subsequently, however, there was a decrease in endo thelial cell proliferation, which was reduced to levels below those of sham -treated animals, in conjunction with interstitial expression of the antian giogenic factor thrombospondin-1 (TSP-1) and decreased tubular expression o f the proangiogenic factor vascular endothelial growth factor (VEGF). Both the increase in TSP-1 expression and the loss of VEGF expression were corre lated with capillary loss and the development of glomerulosclerosis and int erstitial fibrosis. Progressive macrophage infiltration was correlated both spatially and quantitatively with the sites of absent or diminished VEGF e xpression. In addition, macrophage-associated cytokines (interleukin-1 beta , interleukin-6, and tumor necrosis factor-alpha) inhibited VEGF mRNA expre ssion and protein secretion by cultured tubular epithelial cells of the med ullary thick ascending limb, under both normoxic and hypoxic conditions. Im paired angiogenesis characterizes the remnant kidney model and is correlate d with progression. The impaired angiogenesis may he mediated by alteration s in the renal expression of TSP-1 and VEGF, with the latter being regulate d by macrophage-associated cytokines.