The effect of androgens on angiotensin II-renal responses in hypertension.

摘要

Androgens play a key role in the gender-associated blood pressure regulation. Previous studies suggested that the kidney is one target for androgen modulation of blood pressure. The kidney is an important organ for long-term blood pressure regulation. The renal vasculature not only contributes to peripheral vascular resistance, but also modulates sodium and water balance. Evidence from hypertensive animal studies suggests that hypertension is due, in part, to enhanced effects of angiotensin II (Ang II) on the renal vasculature. This dissertation project tested the hypothesis that androgens modulate renal vascular responses to Ang II, which may contribute to the pro-hypertensive effect of androgens in New Zealand genetically hypertensive rats (NZGH).; Our current studies showed that castration had antihypertensive effects, whereas testosterone replacement restored blood pressure in castrated male NZGH. Androgens augmented blood pressure responses to both Ang II and Ang II type-1 receptor (AT1) inhibition, suggesting a systemic effect of androgens on vascular reactivity. Renal vascular responses to Ang II were also increased in androgen-replete rats compared to androgen-deplete rats. However, neither protein nor mRNA expression of AT1 was changed by androgens, indicating that the functional differences in response to Ang II amongst the three groups of NZGH rats were not related to changes in expression of the receptor but may be linked to the postreceptor signaling mechanisms.; Rho kinase and protein kinase C (PKC)-CPI-17 are two major signaling pathways, which increase Ca2+ sensitivity during Ang II-induced vascular smooth muscle (VSM) contraction. Treatment with a Rho kinase inhibitor, fasudil, significantly diminished the differential pressor and renal vascular responses to Ang II observed amongst the androgen-replete and androgen-deplete groups. Both protein expression and activity of Rho kinase were greater in androgen-replete groups than in the castrated group. The differential responses to Ang II infusion caused by androgens were also markedly attenuated by treatment with the PKC inhibitor, chelerythrine. Androgens increased mRNA expression of some PKC isoforms and protein amount for both total and phosphorylated CPI-17. These data suggest that these two signaling pathways contribute to androgen amplification of Ang II-renal vasoconstriction.; In summary, the data from this project support the hypothesis that androgens exacerbate hypertension, at least partly, via potentiation of renal vascular responses to Ang II resulting from androgen interactions with AT1 receptor signaling mechanisms.