Role of Kidneys in Sex Differences in Angiotensin II-Induced Hypertension

The significance of kidneys in regulation of sodium and water balance and hemodynamics has been demonstrated both in patients and animal models. In the present study, we tested our hypothesis that kidneys play an essential role in control of sex differences in angiotensin II (Ang II)-dependent hypertension. Kidney transplantations (KTXs) were performed between male (M) and female (F) C57BL/6 mice (donorrecipient: F -> F, M -> M, F -> M, and M -> F). Radiotelemetry transmitters were implanted for measurement of mean arterial pressure during the infusion of Ang II (600 ng.kg(-1).min(-1)). Gene expressions and inflammatory responses in the transplanted grafts were assessed. We found that same-sex-KTX mice still exhibited sex differences in Ang II-dependent hypertension (31.3 +/- 0.8 mmHg in M -> M versus 12.2 +/- 0.6 mmHg in F -> F), which were reduced between males and females when they received kidneys of the opposite sex (32.9 +/- 1 mmHg in M -> F versus 22.3 +/- 0.7 mmHg in F -> M). The sex differences in gene expressions, including AT(1)R (angiotensin II receptor, type 1), AT(1)R/AT(2)R, ET-1 (endothelin-1), ETA (endothelin receptor type A), NHE3 (sodium-hydrogen exchanger 3), alpha-ENaC (alpha-epithelial sodium channel), and gamma-ENaC, were unaltered in same-sex KTXs and much lessened in cross-sex KTXs. In addition, the cross-sex KTXs exhibited more robust inflammatory responses reflected by higher expression of IL-6 (interleukin 6), TNF alpha (tumor necrosis factor alpha), and KC (keratinocyte-derived chemokine) than same-sex KTX. Our results indicate that kidneys play an essential role in sex differences of Ang II-dependent hypertension. KTX of male kidneys to females augmented the blood pressure response, whereas KTX of female kidneys to males attenuated the blood pressure response. The host's extrarenal systems modulate expressions of many genes and inflammatory response, which may also contribute to the sex differences in blood pressure regulation.