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

Conclusions. We suggest that proinflammatory chemoatIncreased renal expression of monocyte chemoattractant protractants have a role in the development of interstitial inflamtein-1 and osteopontin in ADPKD in rats. mation and renal failure in ADPKD. 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. Evi- The polycystic kidney diseases (PKDs) are characterdence suggests that interstitial inflammation may be important ized by the development of fluid-filled, epithelial-lined in the development of ESRD in ADPKD. Han:SPRD rats cysts derived from renal tubules. PKD can be inherited manifest ADPKD that resembles the human disease. Homozygous cystic (Cy/Cy) rats develop rapidly progressive PKD and or acquired. Autosomal-dominant (AD) PKD, the most die near age 3 weeks. Heterozygous (Cy/) females develop common form seen in humans [1, 2], has a highly variable slowly progressive PKD without evidence of renal dysfunction onset and renal failure occurs in approximately 50% of until the second year of life, whereas heterozygous (Cy/) affected individuals [1]. There is growing awareness that males develop more aggressive PKD with renal failure beginthe rate of disease progression is dependent to a signifining by 8 to 12 weeks of age. Methods. To examine the relationship between proinflam- cant extent upon epigenetic factors that contribute to matory chemoattractants and the development of interstitial cyst growth, interstitial inflammation and progressive fiinflammation and ultimately renal failure in ADPKD, we eval- brosis. uated monocyte chemoattractant protein-1 (MCP-1) and osteo- In 1989, Kaspareit-Rittinghausen et al described a ropontin mRNAs and proteins in kidneys from Han:SRPD rats. dent model of PKD, the Han:SPRD, which arose spontaResults. MCP-1 and osteopontin mRNAs, expressed at low levels in kidneys from normal (/) animals at all ages, were neously in Sprague-Dawley rats [3]. PKD in the Han: markedly elevated in kidneys from 3-week-old Cy/Cy animals. SPRD rat is inherited as an autosomal dominant trait, In kidneys from heterozygous (Cy/) adults of either gender, but there is a gene dose effect. Rats of either gender that MCP-1 and osteopontin mRNAs were more abundant than inherit two abnormal genes develop rapidly progressive normal; MCP-1 mRNA was more abundant in Cy/ males PKD and die with renal failure at approximately three than in females. Thus, chemoattractant mRNA expression correlated with the development of renal failure in Cy/Cy and weeks of age [3, 4]. Heterozygous animals develop slowly Cy/ rats. Osteopontin mRNA, localized by in situ hybridiza- progressive PKD that resembles in many respects human tion, was moderately expressed in the renal medulla of normal ADPKD [4, 5]. In heterozygous Han:SPRD rats, the animals; however, this mRNA was expressed at very high levels gender effect is exaggerated in comparison to the human in the cystic epithelia of Cy/ and Cy/Cy animals. MCP-1 counterpart. Male heterozygotes develop severe renal and osteopontin proteins, localized by immunohistochemistry, cystic changes and renal insufficiency soon after sexual were weakly detected in / kidneys but were densely expressed in Cy/Cy and in adult Cy/ kidneys, primarily over maturity, and die with renal failure by 12 to 14 months of cystic epithelium. Increased expression of chemoattractants age [4, 5]. Extensive interstitial inflammation and fibrosis was associated with the accumulation of ED-1 positive cells develops in conjunction with the onset of renal insuffi(macrophages) in the interstitium of cystic kidneys. ciency in male heterozygotes [4, 5]. In contrast, the renal cysts and interstitial changes progress more slowly in female heterozygotes [4] and death from renal insuffi