Formyl Peptide Receptor Blockade Ameliorates Intrarenal Resistance Artery Function and Decreases Blood Pressure in SHR

Abstract

AimsIt is well established that chronic activation of the immune system 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 they still use 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‐MITs) 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 blood pressure and kidney injury in SHR. We hypothesized that F‐MITs, released due to low‐grade chronic trauma, activate FPR and contribute to elevated blood pressure and intrarenal artery dysfunction in SHR.MethodsTwelve‐week old male SHR were treated for 10 days with FPR antagonist cocktail: FPR 1 antagonist Cyclosporin H (CsH, 0.1 mg/kg/day) and FPR 2 antagonist WRW4 (0.1 mg/kg/day). Blood pressure was measured by telemetry. Distal interlobar arteries and mesenteric resistance arteries (diameter < 300 μm) were isolated and mounted in a wire myograph to evaluate vascular function. Western blot and confocal microscopy were used to investigate FPR protein expression. To evaluate if F‐MITs infusion in normotensive rats leads to changes in FPR pathway in intrarenal arteries as observed in SHR, Wistar rats were treated with F‐MITs (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‐MITs, intrarenal arteries were also isolated from control rats and treated ex vivo with F‐MITs (100 nM) or non‐formylated peptide.Results and ConclusionFPR blockade decreased mean arterial pressure (SHR+vehicle: 151±7.2 vs. SHR+CsH+WRW4: 138±0.4 mmHg, p<0.05) and left ventricle mass from SHR, but did not change heart rate. Also, FPR blockade ameliorated acetylcholine‐induced relaxation in both intrarenal (Emax: SHR+vehicle: 10±5 vs. SHR+CsH+WRW4: 28±6 %, p<0.05) and mesenteric (Emax: SHR+vehicle: 74±10 vs. SHR+CsH+WRW4: 99±0.6 %, p<0.05) resistance arteries. Indomethacin, cyclooxygenase inhibitor (10 μM), incubation improved acetylcholine‐induced relaxation only in arteries from SHR treated with vehicle. No differences in noradrenaline‐induced contraction or sodium nitroprusside‐induced relaxation were observed. In intrarenal arteries from untreated SHR, we found that FPR protein expression was higher (1.5‐fold vs. Wistar Kyoto, WKY), while β‐arrestin 2 (protein that internalizes FPR upon activation) protein expression was decreased (2‐fold vs. WKY). Additionally, it was observed that the co‐localization of FPR and β‐arrestin 2 was decreased in intrarenal arteries from SHR. Similarly, F‐MITs treatment in vivo increased intrarenal artery FPR protein expression (2.3‐fold vs. control) and decreased β‐arrestin 2 and phosphorylation of endothelial nitric oxide synthase (4‐fold vs. control). These results were reproduced in isolated arteries incubated with F‐MITs or control for 6 h ex vivo. Overall, these data suggest that FMITs play a role in hypertension via FPR activation. These peptides can be a putative target for therapeutic treatment of hypertension.Support or Funding InformationAmerican Heart Association (AHA) and National Institutes of Health (NIH)