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

Research output: Contribution to journalArticle

222 Citations (Scopus)

Abstract

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 (US)
Pages (from-to)601-611
Number of pages11
JournalAmerican Journal of Kidney Diseases
Volume37
Issue number3
StatePublished - 2001

Fingerprint

Thrombospondin 1
Vascular Endothelial Growth Factor A
Kidney
Microvessels
Staining and Labeling
Fibrosis
Endothelial Cells
Osteopontin
Proteins
Macrophages
Cell Proliferation

Keywords

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

ASJC Scopus subject areas

  • Nephrology

Cite this

Kang, D. H., Anderson, S., Kim, Y. G., Mazzalli, M., Suga, S. I., Jefferson, J. A., ... Johnson, R. J. (2001). Impaired angiogenesis in the aging kidney: Vascular endothelial growth factor and thrombospondin-1 in renal disease. American Journal of Kidney Diseases, 37(3), 601-611.

Impaired angiogenesis in the aging kidney : Vascular endothelial growth factor and thrombospondin-1 in renal disease. / Kang, Duk Hee; Anderson, Sharon; Kim, Yoon Goo; Mazzalli, Marilda; Suga, Shin ichi; Jefferson, J. Ashley; Gordon, Katherine L.; Oyama, Terry T.; Hughes, Jeremy; Hugo, Christian; Kerjaschki, Dontsho; Schreiner, George F.; Johnson, Richard J.

In: American Journal of Kidney Diseases, Vol. 37, No. 3, 2001, p. 601-611.

Research output: Contribution to journalArticle

Kang, DH, Anderson, S, Kim, YG, Mazzalli, M, Suga, SI, Jefferson, JA, Gordon, KL, Oyama, TT, Hughes, J, Hugo, C, Kerjaschki, D, Schreiner, GF & Johnson, RJ 2001, 'Impaired angiogenesis in the aging kidney: Vascular endothelial growth factor and thrombospondin-1 in renal disease', American Journal of Kidney Diseases, vol. 37, no. 3, pp. 601-611.
Kang, Duk Hee ; Anderson, Sharon ; Kim, Yoon Goo ; Mazzalli, Marilda ; Suga, Shin ichi ; Jefferson, J. Ashley ; Gordon, Katherine L. ; Oyama, Terry T. ; Hughes, Jeremy ; Hugo, Christian ; Kerjaschki, Dontsho ; Schreiner, George F. ; Johnson, Richard J. / Impaired angiogenesis in the aging kidney : Vascular endothelial growth factor and thrombospondin-1 in renal disease. In: American Journal of Kidney Diseases. 2001 ; Vol. 37, No. 3. pp. 601-611.
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TY - JOUR

T1 - Impaired angiogenesis in the aging kidney

T2 - Vascular endothelial growth factor and thrombospondin-1 in renal disease

AU - Kang, Duk Hee

AU - Anderson, Sharon

AU - Kim, Yoon Goo

AU - Mazzalli, Marilda

AU - Suga, Shin ichi

AU - Jefferson, J. Ashley

AU - Gordon, Katherine L.

AU - Oyama, Terry T.

AU - Hughes, Jeremy

AU - Hugo, Christian

AU - Kerjaschki, Dontsho

AU - Schreiner, George F.

AU - Johnson, Richard J.

PY - 2001

Y1 - 2001

N2 - 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.

AB - 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.

KW - Aging

KW - Angiogenesis

KW - Capillary rarefaction

KW - Thrombospondin-1 (TSP-1)

KW - Vascular endothelial growth factor (VEGF)

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