Abstract 069: Intrarenal Arteries Sense Mitochondrial N-formyl Peptides via Formyl Peptide Receptor in Wistar and Spontaneously Hypertensive Rats (shr)
It is well established that chronic immune system activation contributes to hypertension and kidney injury. Mitochondria carry hallmarks of their bacterial ancestry and thus have emerged as a significant source of inflammatogenic damage-associated molecular patterns (DAMPs). One of these hallmarks is that it still uses an N-formyl-methionyl-tRNA as an initiator of protein synthesis. Recently, we have observed that mitochondrial DAMPs are elevated in the circulation of SHR, and that mitochondrial N-formyl peptides (F-MIT) infusion in rats induces systemic inflammation and vascular dysfunction via formyl peptide receptor (FPR) activation. However, we do not know if FPR plays a role in kidney injury and hypertension. We hypothesized that F-MIT activate FPR and lead to intrarenal dysfunction in 12 week old male Wistar and SHR (n=4-8). Wistar rats were treated with F-MIT (0.02 mg/kg) or non-formylated peptide (control) for 6 h and intrarenal arteries (diameter >100 μm) were isolated. To exclude systemic effects of F-MIT, intrarenal arteries were also isolated from control rats and treated ex vivo with 100 nM F-MIT or non-formylated peptide. F-MIT treatment in vivo increased intrarenal arteries FPR protein expression (2.3-fold vs. control) and decreased β-arrestin 2 (protein that internalizes FPR upon activation) and phosphorylation of endothelial nitric oxide synthase (4-fold vs. control). These results were reproduced in isolated arteries incubated with F-MIT or control for 6 h ex vivo. Similarly, in intrarenal arteries from untreated SHR, we found that FPR protein expression was higher (1.5-fold vs. Wistar Kyoto, WKY) and β-arrestin 2 protein expression was decreased (2-fold vs. WKY). Interestingly, although treatment with hydrochlorothiazide (10-55 mg/kg/day) and reserpine (0.6-4.5 mg/kg/day) for 7 weeks attenuated the increase in blood pressure in SHR, anti-hypertensive therapy did not change FPR and β-arrestin 2 protein expression. Additionally, it was observed that the co-localization of FPR and β-arrestin 2 was decreased in intrarenal arteries from SHR. Overall, these data suggest that intrarenal arteries sense F-MIT. Also, FPR activation parameters following F-MIT treatment of normotensive rats are similar to those observed in SHR.
Author Disclosures: C.F. Wenceslau: None. C.G. McCarthy: None. S. Ogbi: None. P.M. O'Connor: None. R. Webb: None.
This research has received full or partial funding support from the American Heart Association, Greater Southeast Affiliate (Alabama, Florida, Georgia, Louisiana, Mississippi, Puerto Rico & Tennessee).
- © 2015 by American Heart Association, Inc.