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.
Highlights
Epidemiological studies have shown that chronic kidney disease (CKD) is a serious risk factor for cardiovascular disease, and that there is a high incidence of death due to cardiovascular events among CKD patients [1]
To evaluate their susceptibility to renal injury, we examined RAMP2+/2 mice and their WT littermates in a STZ-induced diabetic nephropathy model
Consistent with that finding, the expressions of calcitonin-receptor-like receptor (CLR) and RAMPs reportedly increase with progression of renal fibrosis in experimental models of CKD [44,45]
Summary
Epidemiological studies have shown that chronic kidney disease (CKD) is a serious risk factor for cardiovascular disease, and that there is a high incidence of death due to cardiovascular events among CKD patients [1]. During the progression of CKD, damage caused by uremic toxins can degrade renal function. It was recently reported that the uremic toxin indoxyl sulfate induces endoplasmic reticulum (ER) stress that can aggravate CKD, renal tubule injury [2]. It is recognized that chronic albuminuria, a major symptom of CKD, is a detrimental factor that promotes CKD by enhancing ER stress and injuring tubule cells [3]. The UPR works to maintain cellular homeostasis, but when the stress is excessive it can lead to cell death [5] and to disease [6,7]. An exaggerated ER stress response contributes to kidney disease due to glomerular and tubular damage [8]. Controlling ER stress could be an effective approach to breaking the vicious cycle of CKD progression
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