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

Duk Hee Kang, Sharon Anderson, Yoon Goo Kim, Marilda Mazzalli, Shin ichi Suga, J. Ashley Jefferson, Katherine L. Gordon, Terry T. Oyama, Jeremy Hughes, Christian Hugo, Dontsho Kerjaschki, George F. Schreiner, Richard J. Johnson

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263 Scopus citations


We investigated the relationship of changes in the microvasculature to age-related structural and functional changes in the kidney to determine whether there was evidence of impaired angiogenesis and whether the loss of microvasculature could be accounted for by changes in the local production of angiogenic or antiangiogenic factors. Glomerular and peritubular capillary number, density, and endothelial cell proliferation were determined in aging (24 months; n = 9) and young (3 months; n = 8) rat kidneys and correlated with renal functional and structural changes and alterations in renal expression of vascular endothelial growth factor (VEGF) and thrombospondin-1 (TSP-1). Aging rats showed a focal decrease in both peritubular capillary (peritubular capillary staining, 5.4% ± 1.8% versus 11.3% ± 2.0% per 100 tubules; rarefaction index, 10.6% ± 4.6% 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 in aging rats compared with young rats (glomerular, 0.04 ± 0.01 versus 0.15 ± 0.03 positive cells/glomerular cross-section; peritubular, 0.7 ± 0.2 versus 4.3 ± 2.6 positive cells/mm2; P < 0.05). In the aging kidney, VEGF expression was focally increased in the cortex compared with young rats, 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 density (r2 = 0.57; P < 0.01) and inversely correlated with tubular osteopontin (r2 = -0.55; P < 0.05) and macrophage infiltration (r2 = -0.64; P < 0.01). TSP-1 staining was increased in the glomeruli and tubulointerstitium of the aging rats. Glomerular TSP-1 score correlated inversely with glomerular capillary number (r2 = -0.89; P < 0.001). Tubulointerstitial TSP-1 also correlated with percentage of positive staining of peritubular capillary (r2 = -0.59; P < 0.001). Glomerular capillary number showed significant correlation with glomerulosclerosis score, as well as with 24-hour urinary protein excretion. Peritubular capillary density also inversely correlated with interstitial fibrosis score and urinary protein excretion. In conclusion, 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 suggest that impaired angiogenesis associated with progressive loss in renal microvasculature may have a pivotal role in age-related nephropathy.

Original languageEnglish
Pages (from-to)601-611
Number of pages11
JournalAmerican Journal of Kidney Diseases
Issue number3
StatePublished - 2001

Bibliographical note

Funding Information:
Supported in part by grants no. DK-43422, DK-52121, DK-47695 (R.J.J.) and AG 14699 (S.A.) from the National Institutes of Health and an International Fellowship Award of the International Society of Nephrology, the Postdoctoral Training Program of the Korean Science and Engineering Foundation, and the Grant from Alumni Association of Ewha Women’s University, College of Medicine, Seoul, Korea (D-H.K.).


  • Aging
  • Angiogenesis
  • Capillary rarefaction
  • Thrombospondin-1 (TSP-1)
  • Vascular endothelial growth factor (VEGF)


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