The 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 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.
Soluble receptor for advanced glycation end products protects from ischemia- and reperfusion-induced acute kidney injury
- Award Group:
- Funder(s): Japan Society for the Promotion of Science
- Award Id(s): grant number 19K23941
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- Accepted Manuscript 23 November 2021
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Taro Miyagawa, Yasunori Iwata, Megumi Oshima, Hisayuki Ogura, Koichi Sato, Shiori Nakagawa, Yuta Yamamura, Yasutaka Kamikawa, Taito Miyake, Shinji Kitajima, Tadashi Toyama, Akinori Hara, Norihiko Sakai, Miho Shimizu, Kengo Furuichi, Seiichi Munesue, Yasuhiko Yamamoto, Shuichi Kaneko, Takashi Wada; Soluble receptor for advanced glycation end products protects from ischemia- and reperfusion-induced acute kidney injury. Biol Open 2021; bio.058852. doi: https://doi.org/10.1242/bio.058852
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