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

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


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenomedullin / genetics
  • Adrenomedullin / metabolism*
  • Animals
  • Antibiotics, Antineoplastic / adverse effects
  • Antibiotics, Antineoplastic / pharmacology
  • Cell Death / drug effects
  • Cell Death / genetics
  • Cell Line
  • Endoplasmic Reticulum Stress
  • Humans
  • Kidney Diseases / chemically induced
  • Kidney Diseases / genetics
  • Kidney Diseases / metabolism*
  • Kidney Diseases / pathology
  • Kidney Glomerulus / injuries
  • Kidney Glomerulus / metabolism
  • Kidney Glomerulus / pathology
  • Kidney Tubules, Proximal / injuries
  • Kidney Tubules, Proximal / metabolism*
  • Kidney Tubules, Proximal / pathology
  • Mice
  • Mice, Knockout
  • Receptor Activity-Modifying Protein 2 / genetics
  • Receptor Activity-Modifying Protein 2 / metabolism*
  • Streptozocin / adverse effects
  • Streptozocin / pharmacology
  • eIF-2 Kinase / genetics
  • eIF-2 Kinase / metabolism


  • Antibiotics, Antineoplastic
  • RAMP2 protein, human
  • Ramp2 protein, mouse
  • Receptor Activity-Modifying Protein 2
  • Adrenomedullin
  • Streptozocin
  • EIF2AK3 protein, human
  • PERK kinase
  • eIF-2 Kinase

Grant support

This study was supported by the Funding Program for Next Generation World-Leading Researchers (NEXT Program) from the Cabinet Office, Government of Japan, Research Grant for Cardiovascular Disease from the National Cardiovascular Center, Research grant from the Naito Foundation, SENSHIN Medical Research Foundation,the NOVARTIS Foundation (Japan) for the Promotion of Science,Novartis Foundation for Gerontological Research, and Japan vascular disease research foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.