Graduate Student University of Toronto Toronto, Ontario, Canada
Background: Hypertension [HTN] has been associated with levels of B cell-derived immunoglobulins, particularly IgA. In spontaneously hypertensive rat [SHR], increases in blood pressure [BP] were observed after experimental induction of IgA production via flagellin exposure, implicating IgA quiescence in the maintenance of lower BP in this model. Indeed, we found IgA knockout [-/-] mice exhibited lower baseline systolic BP [SBP] and increased urine- and sodium-excretion compared to controls. Here, we explore the effects of genetic IgA-deficiency in angiotensin-II [Ang-II]-induced HTN.
METHODS AND RESULTS: 10-12 wk old IgA-/- and IgA+/+ littermate controls were administered Ang-II (500 ng/kg/min) via osmotic minipumps for 28d. When IgA-/- and littermate IgA+/+ controls showed no difference in SBP after Ang-II (150±18 vs. 135±22 mmHg; N=5/group; p=0.75), we hypothesized that IgA transfer between co-housed animals may underlie this unexpected result.
To address this, we generated separately housed IgA-/- and IgA+/+ offspring by separately crossing IgA-/- females with IgA-/- males and IgA+/+ females with IgA+/+ males. In this setting, IgA-/- offspring showed blunted SBP response to Ang-II vs. IgA+/+ offspring (103±18 vs. 152±14 mmHg; N=5-9/group; p< 0.0001), demonstrating that passive IgA transfer through breast milk or coprophagy is sufficient to permit Ang-II-induced HTN.
Next, we crossed IgA-/- females with heterozygous IgA+/- males and separated offspring by genotype at weaning to generate litters containing both IgA-/- and IgA+/- offspring, allowing for direct comparison of BP responses to Ang-II within the same maternal environment. This approach minimized confounding variables related to differences in maternal factors and early-life exposures, ensuring observed differences are due to IgA genotype. 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 in response to Ang-II when not receiving IgA via breast milk.
Conclusion: Co-housing significantly influences SBP responses in mice, likely due to passive IgA transfer through either coprophagy or maternal breast milk. Separation by genotype at the time of weaning confirmed that loss of IgA results in a blunted hypertensive response to Ang-II, underscoring the critical role of IgA in this model of HTN. Ongoing studies aim to determine whether these effects are mediated by changes in mucosal immunity and gut microbiome.
