Impaired angiogenesis in the aging kidney: Vascular endothelial growth factor and thrombospondin-1 in renal disease

We investigated the relationship of changes in the microvasculature to age- related structural and functional changes in the kidney to determine whethe r there was evidence of impaired angiogenesis and whether the loss of micro vasculature could be accounted for by changes in the local production of an giogenic or antiangiogenic factors. Glomerular and peritubular capillary nu mber, density, and endothelial cell proliferation were determined in aging (24 months; n = 9) and young (3 months; n = 8) rat kidneys and correlated w ith renal functional and structural changes and alterations in renal expres sion of vascular endothelial growth factor (VEGF) and thrombospondin-1 (TSP -1). Aging rats showed a focal decrease in both peritubular capillary (peri tubular capillary staining, 5.4% +/- 1.8% versus 11.3% +/- 2.0% per 100 tub ules; rarefaction index, 10.6% +/- 4.5% versus 0.6% +/- 0.1%, aging versus young rats; P < 0.05 and P < 0.001, respectively) and glomerular capillary loops (27.3 +/- 6.9 versus 50.7 +/- 7.4/glomerulus, aging versus young rats ; P < 0.001). The number of proliferating endothelial cells was decreased i n aging rats compared with young rats (glomerular, 0.04 +/- 0.01 versus 0.1 5 +/- 0.03 positive cells/glomerular cross-section; peritubular, 0.7 +/- 0. 2 versus 4.3 +/- 2.8 positive cells/mm(2); P < 0.05). In the aging kidney, VEGF expression was focally increased in the cortex compared with young rat s, whereas a profound decrease was observed in the outer and inner medulla (total area of VEGF expression, 19.2% +/- 11.4% versus 39.3% +/- 7.6%; P < 0.05). Tubular VEGF expression correlated with peritubular capillary densit y (r(2) = 0.57; P < 0.01) and inversely correlated with tubular osteopontin (r(2) = -0.55; P < 0.05) and macrophage infiltration (r(2) = -0.64; P < 0. 01). TSP-1 staining was increased in the glomeruli and tubulointerstitium o f the aging rats. Glomerular TSP-1 score correlated inversely with glomerul ar capillary number (r(2) = -0.89; P < 0.001). Tubulointerstitial TSP-1 als o correlated with percentage of positive staining of peritubular capillary (r(2) = -0.59; P < 0.001). Glomerular capillary number showed significant c orrelation with glomerulosclerosis score, as well as with 24-hour urinary p rotein excretion. Peritubular capillary density also inversely correlated w ith interstitial fibrosis score and urinary protein excretion. In conclusio n, glomerular and peritubular capillary loss in the aging kidney correlate with alterations in VEGF and TSP-1 expression and also with the development of glomerulosclerosis and tubulointerstitial fibrosis. These findings sugg est that impaired angiogenesis associated with progressive loss in renal mi crovasculature may have a pivotal role in age-related nephropathy. (C) 2001 by the National Kidney Foundation, Inc.