Abstract Body (Do not enter title and authors here): 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.