title: Adrenomedullin-RAMP2 system suppresses ER stress-induced tubule cell death and is involved in kidney protection.
abstract: Various bioactive peptides have been implicated in the homeostasis of organs and tissues. Adrenomedullin (AM) is a peptide with various bioactivities. AM-receptor, calcitonin-receptor-like receptor (CLR) associates with one of the subtypes of the accessory proteins, RAMPs. Among the RAMP subisoforms, only RAMP2 knockout mice ⁻/⁻ reproduce the phenotype of embryonic lethality of AM⁻/⁻, illustrating the importance of the AM-RAMP2-signaling system. Although AM and RAMP2 are abundantly expressed in kidney, their function there remains largely unknown. We used genetically modified mice to assess the pathophysiological functions of the AM-RAMP2 system. RAMP2⁺/⁻ mice and their wild-type littermates were used in a streptozotocin (STZ)-induced renal injury model. The effect of STZ on glomeruli did not differ between the 2 types of mice. On the other hand, damage to the proximal urinary tubules was greater in RAMP2⁺/⁻. Tubular injury in RAMP2⁺/⁻ was resistant to correction of blood glucose by insulin administration. We examined the effect of STZ on human renal proximal tubule epithelial cells (RPTECs), which express glucose transporter 2 (GLUT2), the glucose transporter that specifically takes up STZ. STZ activated the endoplasmic reticulum (ER) stress sensor protein kinase RNA-like endoplasmic reticulum kinase (PERK). AM suppressed PERK activation, its downstream signaling, and CCAAT/enhancer-binding homologous protein (CHOP)-induced cell death. We confirmed that the tubular damage was caused by ER stress-induced cell death using tunicamycin (TUN), which directly evokes ER stress. In RAMP2⁺/⁻ kidneys, TUN caused severe injury with enhanced ER stress. In wild-type mice, TUN-induced tubular damage was reversed by AM administration. On the other hand, in RAMP2⁺/⁻, the rescue effect of exogenous AM was lost. These results indicate that the AM-RAMP2 system suppresses ER stress-induced tubule cell death, thereby exerting a protective effect on kidney. The AM-RAMP2 system thus has the potential to serve as a therapeutic target in kidney disease.
authors: Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Matsumoto, Japan.
authors: Ryuichi
authors: R
authors: Uetake
authors: Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Matsumoto, Japan.
authors: Takayuki
authors: T
authors: Sakurai
authors: Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Matsumoto, Japan.
authors: Akiko
authors: A
authors: Kamiyoshi
authors: Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Matsumoto, Japan.
authors: Yuka
authors: Y
authors: Ichikawa-Shindo
authors: Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Matsumoto, Japan.
authors: Hisaka
authors: H
authors: Kawate
authors: Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Matsumoto, Japan.
authors: Yasuhiro
authors: Y
authors: Iesato
authors: Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Matsumoto, Japan.
authors: Takahiro
authors: T
authors: Yoshizawa
authors: Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Matsumoto, Japan.
authors: Teruhide
authors: T
authors: Koyama
authors: Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Matsumoto, Japan.
authors: Lei
authors: L
authors: Yang
authors: Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Matsumoto, Japan.
authors: Yuichi
authors: Y
authors: Toriyama
authors: Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Matsumoto, Japan.
authors: Akihiro
authors: A
authors: Yamauchi
authors: Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Matsumoto, Japan.
authors: Kyoko
authors: K
authors: Igarashi
authors: Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Matsumoto, Japan.
authors: Megumu
authors: M
authors: Tanaka
authors: Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors: Takashige
authors: T
authors: Kuwabara
authors: Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, Kyoto, Japan ; Medical Innovation Center, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors: Kiyoshi
authors: K
authors: Mori
authors: Department of Nephrology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors: Motoko
authors: M
authors: Yanagita
authors: Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors: Masashi
authors: M
authors: Mukoyama
authors: Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Matsumoto, Japan.
authors: Takayuki
authors: T
authors: Shindo
mesh_terms: D053607:Adrenomedullin / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000009:adverse effects / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects / Q000235:genetics; D002460:Cell Line; D059865:Endoplasmic Reticulum Stress; D006801:Humans; D007674:Kidney Diseases / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D007678:Kidney Glomerulus / Q000293:injuries / Q000378:metabolism / Q000473:pathology; D007687:Kidney Tubules, Proximal / Q000293:injuries / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D058263:Receptor Activity-Modifying Protein 2 / Q000235:genetics / Q000378:metabolism*; D013311:Streptozocin / Q000009:adverse effects / Q000494:pharmacology; D019892:eIF-2 Kinase / Q000235:genetics / Q000378:metabolism
chemical_list: D053607:Adrenomedullin; D000903:Antibiotics, Antineoplastic; D058263:Receptor Activity-Modifying Protein 2; D013311:Streptozocin; D019892:eIF-2 Kinase; C545503:RAMP2 protein, human; C545506:Ramp2 protein, mouse; C460640:EIF2AK3 protein, human