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Sex-related differences in the intratubular renin-angiotensin system (RAS) in 2-kidney 1-clip hypertensive rats.

The intratubular renin-angiotensin system(RAS) is thought to play an essential role in hypertensive renal disease, but information regarding sex-related differences in this system is limited. This study investigated sex differences in the intratubular RAS in 2-kidney 1-clip(2K1C) rats. A 2.5-mm clip was placed on the left renal artery of Sprague Dawley rats, and the rats were euthanized 3 or 5 weeks following the operation. The systolic blood pressure(SBP) increased in the 2K1C rats in both sexes but was significantly higher in the males than the females, and an antihypertensive effect was not observed in 2K1C ovariectomized(OVX) female rats. Compared with the male 2K1C rats, intratubular angiotensin-converting enzyme(ACE) and Ang II were repressed, and intratubular ACE2, Ang 1-7 and MasR were increased in both kidneys in the female 2K1C rats 5 weeks after surgery. Comparison with the male and female rats, the intratubular mRNA levels of ACE and AT1R were augmented in the OVX female rats regardless of the clipping surgery 3 weeks post-operation. AT2R was upregulated in the female rats with or without OVX; thus, the AT1/AT2 ratio was higher in the female rats than the male rats. In conclusion, the female rats were protected from hypertensive renal and cardiac injury after renal artery clipping. An increase in intratubular nonclassic RAS(ACE2/angiotensin 1-7/MasR) and a decrease in the AT1/AT2 ratio could limit the adverse effects of classic RAS during renovascular hypertension in female rats, and estrogen is suggested to play a primary role in the regulation of intratubular RAS components.