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 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/mm(2); 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 (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 of the aging rats. Glomerular TSP-1 score correlated inversely with glomerular capillary number (r(2) = -0.89; P < 0.001). Tubulointerstitial TSP-1 also correlated with percentage of positive staining of peritubular capillary (r(2) = -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.
Department of Medicine, Division of Nephrology, University of Washington, Seattle, WA, USA. dkang@bcm.tmc.edu
D H
DH
Kang
S
S
Anderson
Y G
YG
Kim
M
M
Mazzalli
S
S
Suga
J A
JA
Jefferson
K L
KL
Gordon
T T
TT
Oyama
J
J
Hughes
C
C
Hugo
D
D
Kerjaschki
G F
GF
Schreiner
R J
RJ
Johnson
D000375:Aging / Q000473:pathology* / Q000502:physiology*; D000818:Animals; D002452:Cell Count; D002455:Cell Division; D016228:Endothelial Growth Factors / Q000096:biosynthesis*; D004730:Endothelium, Vascular / Q000166:cytology / Q000502:physiology; D007124:Immunoenzyme Techniques; D007668:Kidney / Q000098:blood supply* / Q000378:metabolism / Q000473:pathology; D007674:Kidney Diseases / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology*; D007678:Kidney Glomerulus / Q000098:blood supply / Q000378:metabolism / Q000473:pathology; D007684:Kidney Tubules / Q000098:blood supply / Q000378:metabolism / Q000473:pathology; D008222:Lymphokines / Q000096:biosynthesis*; D018919:Neovascularization, Physiologic; D051381:Rats; D017207:Rats, Sprague-Dawley; D019700:Thrombospondin 1 / Q000096:biosynthesis*; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D016228:Endothelial Growth Factors; D008222:Lymphokines; D019700:Thrombospondin 1; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors