Activation of Formyl Peptide Receptor Precedes the Onset of Hypertension in Dahl Salt Sensitive Rats: Effects of Microbiota and Salt

Aims Chronic activation of the immune system contributes to kidney injury and hypertension. Mitochondria carry hallmarks of their bacterial ancestry and thus have emerged as a significant source of inflammatogenic damage‐associated molecular patterns. One of these hallmarks is that they still use formylated peptides (NFPs) as an initiator of protein synthesis. NFPs activate formyl peptide receptor (FPR), a G‐protein coupled receptor, and leads to receptor internalization and desensitization. We have observed that mitochondrial NFPs are elevated in the circulation of spontaneously hypertensive rats (SHR) and FPR blockage decreases blood pressure in this strain. Also, we and others observed that FPR downregulates upon activation in immune and non‐immune cells. Given that cell death and gut dysbiosis are present in salt sensitive hypertension, we hypothesized that Dahl sensitive rats would have decreased FPR expression, and that the decrease could be attributed to increased plasma levels of circulating mitochondria and/or bacteria NFPs from the cell death and leaky gut, respectively, and contributes to hypertension. Sex differences were also investigated. Methods Male and Female Dahl Sensitive (S) and Resistant (R) rats (6‐week old) were given a low (0.3% NaCl) or high salt diet (2% NaCl) for 38 days. Rats received normal drinking water or water supplemented with neomycin (0.5 g/l, GIBCO) for 3 weeks. Kidney samples were taken from all rats and used for mRNA extraction and purification. The mRNA was made into cDNA to test gene expression for FPR. Blood was collected to measure mitochondrial NFPs. T‐test *p<0.05; n= 8–11 for Dahl S and R; n=7 for Dahl + neomycin. Results and Conclusion FPR expression was downregulated 4‐fold from male and female Dahl S when compared to Dahl R (AU: FPR mRNA: Dahl R 4.5 ± 1.3 vs. Dahl S: 0.7 ± 0.2*) (Figure 1). This phenomenon was independent of salt and sex differences. Antibiotic treatment partially restored FPR expression from Dahl S animals when compared to Dahl S treated with neomycin (AU FPR mRNA: Dahl S 4.5 ± 1.3 vs. Dahl S‐neomycin treated: 2.74 ± 0.99*). ND6, a mitochondrial protein, is 1.7‐fold higher in plasma from Dahl S compared to Dahl R. Unexpected, salt diet did not change this parameter. We have observed for the first time that FPR is downregulated in Dahl animals independent of salt probably due to overstimulation of this receptor. Therefore, FPR activation due to increased levels of bacterial (NFPs) could be associated with the development of renal injury at an early age independently of salt and elevations in arterial pressure. Support or Funding Information American Heart Association (18POST34060003) and National Institutes of Health (K99GM118885 and R01HL143082) This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .