Impaired angiogenesis in the aging kidney: Vascular endothelial growth factor and thrombospondin-1 in renal disease
Impaired angiogenesis in the aging kidney: Vascular endothelial growth factor and thrombospondin-1 in renal disease
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DOI：
10.1053/ajkd.2001.22087
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发表时间：
2001-03-01
影响因子：
13.2
通讯作者：
Johnson, RJ
中科院分区：
文献类型：
--
作者：
Kang, DH;Anderson, S;Johnson, RJ
我们研究了微血管变化与肾脏年龄相关的结构和功能变化之间的关系，以确定是否存在血管生成受损的证据，以及微血管的丧失是否可以通过局部血管生成或抗血管生成因子的变化来解释。测定老龄大鼠（24月龄，n = 9）和幼龄大鼠（3月龄，n = 8）肾脏肾小球和小管周围毛细血管数量、密度和内皮细胞增殖，并与肾脏功能和结构改变以及肾脏血管内皮生长因子（VEGF）和血小板反应蛋白-1 （TSP-1）表达改变相关。衰老大鼠的小管周围毛细血管（小管周围毛细血管染色，5.4% +/- 1.8%比11.3% +/- 2.0% / 100个小管；稀薄指数，10.6% +/- 4.5%比0.6% +/- 0.1%，衰老大鼠与年轻大鼠相比，分别P < 0.05和P < 0.001）和肾小球毛细血管袢（27.3 +/- 6.9比50.7 +/- 7.4/肾小球，衰老大鼠与年轻大鼠相比，P < 0.001）均出现局灶性减少。与年轻大鼠相比，衰老大鼠的增殖内皮细胞数量减少(肾小球，0.04 +/- 0.01 vs 0.15 +/- 0.03阳性细胞/肾小球横截面；小管周围，0.7 +/- 0.2 vs 4.3 +/- 2.8阳性细胞/mm(2)；P < 0.05)。与幼龄大鼠相比，衰老大鼠肾皮质区VEGF表达增加，外髓和内髓区VEGF表达明显减少（VEGF表达总面积分别为19.2% +/- 11.4%和39.3% +/- 7.6%,P < 0.05）。血管内皮生长因子表达与管周毛细血管密度相关(r(2) = 0.57；P < 0.01)，与小管骨桥蛋白呈负相关(r(2) = -0.55；P < 0.05)和巨噬细胞浸润(r(2) = -0.64；P < 0.01)。衰老大鼠肾小球和小管间质TSP-1染色增多。肾小球TSP-1评分与肾小球毛细血管数目呈负相关(r(2) = -0.89；P < 0.001)。小管间质TSP-1也与小管周围毛细血管阳性染色百分比相关(r(2) = -0.59；P < 0.001)。肾小球毛细血管数目与肾小球硬化评分及24小时尿蛋白排泄量有显著相关性。小管周围毛细血管密度也与间质纤维化评分和尿蛋白排泄呈负相关。总之，衰老肾脏的肾小球和小管周围毛细血管损失与VEGF和TSP-1表达的改变有关，也与肾小球硬化和小管间质纤维化的发生有关。这些发现表明，血管生成受损与肾脏微血管的进行性丧失相关，可能在年龄相关性肾病中起关键作用。(C) 2001年由国家肾脏基金会，Inc。
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% +/- 4.5% 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 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 +/- 2.8 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. (C) 2001 by the National Kidney Foundation, Inc.