Cowley B D, Ricardo S D, Nagao S, Diamond J R
Division of Nephrology & Hypertension, Department of Medicine, Hershey Medical Center, Pennsylvania State University, Hershey, Pennsylvania, USA.
Kidney Int. 2001 Dec;60(6):2087-96. doi: 10.1046/j.1523-1755.2001.00065.x.
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.
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.
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.
We suggest that proinflammatory chemoattractants have a role in the development of interstitial inflammation and renal failure in ADPKD.
人类常染色体显性遗传性多囊肾病（ADPKD）的肾功能恶化速率存在差异，只有约50%的受累个体发展至终末期肾病（ESRD）。有证据表明，间质炎症在ADPKD患者ESRD的发生过程中可能起重要作用。Han:SPRD大鼠表现出与人类疾病相似的ADPKD。纯合子囊性（Cy/Cy）大鼠发生快速进展性PKD，在3周龄左右死亡。杂合子（Cy/+）雌性大鼠发生缓慢进展性PKD，在生命的第二年之前无肾功能障碍的迹象，而杂合子（Cy/+）雄性大鼠发生更具侵袭性的PKD，8至12周龄时开始出现肾衰竭。
为了研究促炎趋化因子与ADPKD中间质炎症的发展以及最终肾衰竭之间的关系，我们评估了Han:SRPD大鼠肾脏中的单核细胞趋化蛋白-1（MCP-1）和骨桥蛋白的mRNA及蛋白水平。
MCP-1和骨桥蛋白的mRNA在各年龄段正常（+/+）动物的肾脏中表达水平较低，而在3周龄的Cy/Cy动物的肾脏中显著升高。在杂合子（Cy/+）成年雌雄大鼠的肾脏中，MCP-1和骨桥蛋白的mRNA比正常情况更为丰富；MCP-1 mRNA在Cy/+雄性大鼠中的表达比雌性大鼠更为丰富。因此，趋化因子mRNA的表达与Cy/Cy和Cy/+大鼠肾衰竭的发展相关。通过原位杂交定位，骨桥蛋白mRNA在正常动物的肾髓质中适度表达；然而，该mRNA在Cy/+和Cy/Cy动物的囊性上皮中高表达。通过免疫组织化学定位，MCP-1和骨桥蛋白在+/+肾脏中弱表达，但在Cy/Cy和成年Cy/+肾脏中高表达，主要在囊性上皮上。趋化因子表达的增加与囊性肾脏间质中ED-1阳性细胞（巨噬细胞）的积聚相关。
我们认为促炎趋化因子在ADPKD间质炎症和肾衰竭的发展中起作用。
