Increased renal expression of monocyte chemoattractant protein-1 and osteopontin in ADPKD in rats

Background. Human autosomal-dominant polycystic kidney disease (ADPKD) is v ariable in the rate of deterioration of renal function, with end-stage rena l disease (ESRD) occurring in only approximately 50% of affected individual s. 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 progressi ve PKD and die near age 3 weeks. Heterozygous (Cy/+) females develop slowly progressive PKD without evidence of renal dysfunction until the second yea r of life, whereas heterozygous (Cy/+) males develop more aggressive PKD wi th renal failure beginning by 8 to 12 weeks of age. Methods. To examine the relationship between proinflammatory chemoattractan ts and the development of interstitial inflammation and ultimately renal fa ilure 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 fr om normal (+/+) animals at all ages, were markedly elevated in kidneys from 3-week-old Cy/Cy animals. In kidneys from heterozygous (Cy/+) adults of ei ther gender, MCP-1 and osteopontin mRNAs were more abundant than normal; MC P-1 mRNA was more abundant in Cy/+ males than in females. Thus, chemoattrac tant mRNA expression correlated with the development of renal failure in Cy /Cy and Cy/+ rats. Osteopontin mRNA, localized by in situ hybridization, wa s moderately expressed in the renal medulla of normal animals; however, thi s mRNA was expressed at very high levels in the cystic epithelia of Cy/+ an d Cy/Cy animals. MCP-1 and osteopontin proteins, localized by immunohistoch emistry, were weakly detected in +/+ kidneys but were densely expressed in Cy/Cy and in adult Cy/+ kidneys, primarily over cystic epithelium. Increase d 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 i n the development of interstitial inflammation and renal failure in ADPKD.