Soluble receptor for advanced glycation end products protects from ischemia- and reperfusion-induced acute kidney injury.

Taro Miyagawa,Yasuhiko Yamamoto,Tadashi Toyama,Koichi Sato,Shiori Nakagawa,Miho Shimizu,Norihiko Sakai,Shuichi Kaneko,Yasutaka Kamikawa,Seiichi Munesue,Yasunori Iwata,Yuta Yamamura,Megumi Oshima,Hisayuki Ogura,Shinji Kitajima,Taito Miyake,Takashi Wada,Kengo Furuichi,Akinori Hara

doi:10.1242/bio.058852

Abstract

ABSTRACTThe full-length receptor for advanced glycation end products (RAGE) is a multiligand pattern recognition receptor. High-mobility group box 1 (HMGB1) is a RAGE ligand of damage-associated molecular patterns that elicits inflammatory reactions. The shedded isoform of RAGE and endogenous secretory RAGE (esRAGE), a splice variant, are soluble isoforms (sRAGE) that act as organ-protective decoys. However, the pathophysiologic roles of RAGE/sRAGE in acute kidney injury (AKI) remain unclear. We found that AKI was more severe, with enhanced renal tubular damage, macrophage infiltration, and fibrosis, in mice lacking both RAGE and sRAGE than in wild-type (WT) control mice. Using murine tubular epithelial cells (TECs), we demonstrated that hypoxia upregulated messenger RNA (mRNA) expression of HMGB1 and tumor necrosis factor α (TNF-α), whereas RAGE and esRAGE expressions were paradoxically decreased. Moreover, the addition of recombinant sRAGE canceled hypoxia-induced inflammation and promoted cell viability in cultured TECs. sRAGE administration prevented renal tubular damage in models of ischemia/reperfusion-induced AKI and of anti-glomerular basement membrane (anti-GBM) glomerulonephritis. These results suggest that sRAGE is a novel therapeutic option for AKI.

Highlights

Acute kidney injury (AKI) is one of the important risk factors for the development of chronic kidney disease and end-stage renal disease (ESRD) [1]
The shedded isoform of receptor for advanced glycation end products (RAGE) and endogenous secretory RAGE, a splice variant, are soluble isoforms that act as organ-protective decoys
We found that acute kidney injury (AKI) was more severe, with enhanced renal tubular damage, macrophage infiltration, and fibrosis, in mice lacking both RAGE and soluble isoforms of RAGE (sRAGE) than in wild-type control mice

Summary

Introduction

Acute kidney injury (AKI) is one of the important risk factors for the development of chronic kidney disease and end-stage renal disease (ESRD) [1]. Renal I/R induces immune responses through inflammatory signaling transductions. Pattern recognition receptors, such as Toll-like receptors, recognize pathogen-related molecules and activate an inflammatory response. A full-length form of the receptor for advanced glycation end products (RAGE) is a multiligand pattern recognition receptor [4]. HMGB1, one of the damage-associated molecular patterns (DAMPs), is a common ligand for RAGE and Toll-like receptors. The full-length signal-transducing RAGE binds DAMPs, eliciting inflammatory reactions; sRAGE captures DAMP-related ligands and inhibits the intracellular signal transductions as a decoy-type receptor [4]. The full-length signal-transducing RAGE binds DAMPs, eliciting inflammatory reactions; sRAGE captures DAMP-related ligands and inhibits the intracellular signal transductions as a decoy-type receptor [4]. sRAGE plays an important role in protecting organs in various pathologic conditions, such as acute lung injury, diabetic atherosclerosis, Alzheimer’s disease, and septic shock [13,14,15,16]

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