Effects of specific genes activating RAGE on polycystic kidney disease.

BACKGROUND: Autosomal-dominant polycystic kidney disease (ADPKD) is characterized by progressive cyst formation and secretion of fluid and is associated with interstitial inflammation and fibrosis, resulting in the loss of renal function. We previously generated mice overexpressing PKD2, causing progressive cyst development with an inflammatory and fibrotic phenotype in the kidneys.

METHODS: To profile the gene expression related to inflammation and cystogenesis, microarray analysis was performed with kidney tissue from 6-, 12- and 18-month-old mice. Subsequently, levels and related mechanisms of selected genes, s100a8 and s100a9, were evaluated.

RESULTS: S100a8 and s100a9 was upregulated more than 2-fold and differently expressed in the cystic region. Receptor of advanced glycation end product (RAGE) is a putative cell surface receptor for s100a8/a9. It was expressed in cyst-lining cells and up-regulated pro-inflammatory transcription factor NF-kappaB in transgenic mice. We also confirmed RAGE expression in ADPKD patient kidneys. It was suggested that the signaling related to proliferative cystogenesis through previous reports; therefore, we confirmed that phosphorylated-ERK and cyst formation was reduced by treatment of RAGE-siRNA.

CONCLUSIONS: The results may provide important information for the expression of s100a8/a9 and RAGE, linking progressive cystogenesis with inflammation in cystic kidney.