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PLoS One. 2014 Feb 5;9(2):e87667. doi: 10.1371/journal.pone.0087667. eCollection 2014.

Adrenomedullin-RAMP2 system suppresses ER stress-induced tubule cell death and is involved in kidney protection.

Author information

1
Department of Cardiovascular Research, Shinshu University Graduate School of Medicine, Matsumoto, Japan.
2
Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, Kyoto, Japan.
3
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.
4
Department of Nephrology, Kyoto University Graduate School of Medicine, Kyoto, Japan.

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.

PMID:
24505304
PMCID:
PMC3914859
DOI:
10.1371/journal.pone.0087667
[Indexed for MEDLINE]
Free PMC Article

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