Soluble receptor for advanced glycation end products inhibits disease progression in autosomal dominant polycystic kidney disease by down-regulating cell proliferation

Abstract

Autosomal polycystic kidney disease (ADPKD) is a highly prevalent genetic renal disorder in which epithelial-lining fluid-filledcysts appear in kidneys. It is accompanied by hyperactivation of cell proliferation, interstitial inflammation, and fibrosis around the cyst lining cells, finally reaching end-stage renal disease. Previously, we found high expression of ligands stimulating the receptor for advanced glycation end products (RAGE) in ADPKD mice. Furthermore, gene silencing of RAGE was revealed to cause reduction of cystogenesis via down-regulation of cell proliferation in vitro, and intravenous administration of anti-RAGE adenovirus in vivo also displayed alleviation of the disease. Here, we attempted to identify the role of soluble RAGE (sRAGE) in inhibiting the progression of ADPKD using 2 different ADPKD mouse models. sRAGE is an endogenously expressed form of RAGE that has no membrane-anchoring domain, thereby giving it the ability to neutralize the ligands that stimulate RAGE signals. Both overexpression of sRAGE and sRAGE treatment blocked RAGE-mediated cell proliferation in vitro. In addition, sRAGE-injected ADPKD mice showed reduced cysts accompanied by enhanced renal function, inhibition of cell proliferation, inflammation, and fibrosis. These positive therapeutic effects of sRAGE displayed little liver toxicity, suggesting it as a new potential therapeutic target of ADPKD with low side effects.-Lee, E. J., Park, E. Y., Mun, H., Chang, E., Ko, J. Y., Kim, D. Y., Park, J. H. Soluble receptor for advanced glycation end products inhibits disease progression in autosomal dominant polycystic kidney disease by down-regulating cell proliferation.