Increased renal expression of monocyte chemoattractant protein-1 and osteopontin in ADPKD in rats
Increased renal expression of monocyte chemoattractant protein-1 and osteopontin in ADPKD in rats
复制标题
DOI：
10.1046/j.1523-1755.2001.00065.x
复制
发表时间：
2001-12-01
影响因子：
19.6
通讯作者：
Diamond, JR
中科院分区：
文献类型：
--
作者：
Cowley, BD;Ricardo, SD;Diamond, JR
背景人类常染色体显性遗传性多囊肾病（ADPKD）在肾功能恶化的速率方面是可变的，仅约50%的受影响个体发生终末期肾病（ESRD）。有证据表明，间质性炎症可能在ADPKD的ESRD发展中起重要作用。Han：SPRD大鼠表现出与人类疾病相似的ADPKD。纯合子囊性（Cy/Cy）大鼠发展为快速进行性PKD，并在接近3周龄时死亡。杂合子（Cy/+）女性发展为缓慢进行性PKD，直到生命的第二年没有肾功能障碍的证据，而杂合子（Cy/+）男性发展为更具侵略性的PKD，肾功能衰竭开始于8至12周龄。为了研究促炎性趋化因子与ADPKD间质炎症发展和最终肾功能衰竭的关系，我们评估了Han：SRPD大鼠肾脏中单核细胞趋化蛋白-1（MCP-1）和骨桥蛋白的mRNA和蛋白质。MCP-1和骨桥蛋白mRNA在所有年龄的正常（+/+）动物的肾脏中以低水平表达，在3周龄Cy/Cy动物的肾脏中显著升高。在两种性别的杂合子（Cy/+）成人的肾脏中，MCP-1和骨桥蛋白mRNA比正常人更丰富; MCP-1 mRNA在Cy/+男性中比女性更丰富。因此，在Cy/Cy和Cy/+大鼠中，趋化因子mRNA表达与肾衰竭的发展相关。骨桥蛋白mRNA，本地化原位杂交，适度表达在正常动物的肾髓质，然而，这种mRNA表达在非常高的水平在囊性上皮细胞的Cy/+和Cy/Cy动物。通过免疫组织化学定位的MCP-1和骨桥蛋白在+/+肾脏中检测到较弱，但在Cy/Cy和成人Cy/+肾脏中密集表达，主要在囊性上皮上。在囊性肾组织中，趋化因子的表达增加与艾德-1阳性细胞（巨噬细胞）的聚集有关。我们认为，促炎性化学引诱物在ADPKD的间质炎症和肾功能衰竭的发展中起作用。
Background. Human autosomal-dominant polycystic kidney disease (ADPKD) is variable in the rate of deterioration of renal function, with end-stage renal disease (ESRD) occurring in only approximately 50% of affected individuals. Evidence suggests that interstitial inflammation may be important in the development of ESRD in ADPKD. Han:SPRD rats manifest ADPKD that resembles the human disease. Homozygous cystic (Cy/Cy) rats develop rapidly progressive PKD and die near age 3 weeks. Heterozygous (Cy/+) females develop slowly progressive PKD without evidence of renal dysfunction until the second year of life, whereas heterozygous (Cy/+) males develop more aggressive PKD with renal failure beginning by 8 to 12 weeks of age.Methods. To examine the relationship between proinflammatory chemoattractants and the development of interstitial inflammation and ultimately renal failure in ADPKD, we evaluated monocyte chemoattractant protein-1 (MCP-1) and osteopontin mRNAs and proteins in kidneys from Han:SRPD rats.Results. MCP-1 and osteopontin mRNAs, expressed at low levels in kidneys from normal (+/+) animals at all ages, were markedly elevated in kidneys from 3-week-old Cy/Cy animals. In kidneys from heterozygous (Cy/+) adults of either gender, MCP-1 and osteopontin mRNAs were more abundant than normal; MCP-1 mRNA was more abundant in Cy/+ males than in females. Thus, chemoattractant mRNA expression correlated with the development of renal failure in Cy/Cy and Cy/+ rats. Osteopontin mRNA, localized by in situ hybridization, was moderately expressed in the renal medulla of normal animals; however, this mRNA was expressed at very high levels in the cystic epithelia of Cy/+ and Cy/Cy animals. MCP-1 and osteopontin proteins, localized by immunohistochemistry, were weakly detected in +/+ kidneys but were densely expressed in Cy/Cy and in adult Cy/+ kidneys, primarily over cystic epithelium. Increased expression of chemoattractants was associated with the accumulation of ED-1 positive cells (macrophages) in the interstitium of cystic kidneys.Conclusions. We suggest that proinflammatory chemoattractants have a role in the development of interstitial inflammation and renal failure in ADPKD.