Abstract 4146438: IgA-Deficiency Attenuates Angiotensin II-Induced Hypertension in Mice

Background: Hypertension [HTN] has been associated with B cell-derived immunoglobulins, particularly IgA. In spontaneously hypertensive rat and humans, IgA has been implicated in HTN pathophysiology, but the mechanisms are not known. Here we explore effects of angiotensin-II [Ang-II]-induced HTN in IgA knockout [ -/- ] mice. Methods&Results: Invasive hemodynamic assessments during anesthesia showed male 10-12 wk old IgA -/- mice to have lower baseline systolic blood pressure [SBP] vs. non -littermate IgA +/+ controls housed separately (86.8±2.1 vs. 104.0±2.7 mmHg; N=18-19/group; p<0.0001). Metabolic studies revealed increased 24-h urine (0.082±0.003 vs. 0.055±0.003 mL/g body weight; N=22-23/group; p<0.0001) and Na + (0.24±0.02 vs. 0.17±0.02 mg/d/g; N=11-12/group; p<0.05) excretion as compared to non -littermate IgA +/+ controls. Next, male 10-12 wk old IgA -/- and IgA +/+ littermate controls received Ang-II (500 ng/kg/min) via osmotic minipumps for 28d. Surprisingly, IgA -/- and littermate IgA +/+ controls showed no differences in SBP in response to Ang-II (150±18 vs. 135±22 mmHg; N=5/group; p=0.75). As mice engage in coprophagy, allowing passive IgA transfer between co-housed littermates, we separately crossed IgA -/- and IgA +/+ females with IgA -/- and IgA +/+ males to yield separately housed IgA -/- and IgA +/+ offspring. In this setting, IgA -/- offspring showed blunted SBP response to Ang-II vs. IgA +/+ offspring (103±18 vs. 152±14 mmHg; N=5/group; p<0.0001), demonstrating how passive IgA transfer via breastmilk or coprophagy permits Ang-II-induced HTN. Finally, we crossed IgA -/- females with heterozygous IgA +/- males and separated offspring by genotype at weaning. In this experiment as well, IgA -/- mice showed an attenuated SBP response to Ang-II vs . co-housed (until weaning) IgA +/+ littermates (106±22 vs. 137±27 mmHg; N=6-9/group; p<0.05), indicating that IgA +/+ mice become hypertensive despite not receiving IgA from breast milk. Conclusion: IgA -/- mice exhibit reduced baseline SBP and increased 24-h Na + and water excretion as compared to separately housed IgA +/+ controls. Co-housing influences SBP responses in mice, likely due to passive IgA transfer. Separating animals by genotype at weaning confirmed loss of the SBP response to Ang-II in IgA -/- mice, highlighting the importance of IgA in Ang-II-induced HTN. Further studies are underway to understand if this effect is mediated by changes in mucosal immunity and microbiome.