Abstract
Enhanced renin-angiotensin activity contributes to hypertension, albuminuria, and glomerular hypertrophy. The angiotensin (Ang)-converting enzyme (ACE) 2/Ang (1-7)/Mas axis pathway acts against Ang II type 1 receptor (AT1R) signaling. We investigated whether olmesartan (Olm), an AT1R blocker, inhibits albuminuria independently of blood pressure and elucidated the potential mechanisms.
Three- to 4-month-old male mice overexpressing renin in the liver (Ren-TG) were given olmesartan (5 mg/kg/day) or hydralazine (Hyd) (3.5 mg/kg/day) orally for 2 months. Ren-TG mice had higher systolic blood pressure (SBP) than wild-type (WT) mice (158.2 ± 6.3 versus 112.8 ± 8.8 mmHg, n = 3-4, P < 0.01). Ren-TG mice treated with Olm or Hyd for 2 months had lower SBP than untreated Ren-TG mice. Urinary albumin excretion (UAE) was significantly increased in Ren-TG mice compared with WT mice (78.2 ± 31.2 versus 28.6 ± 13.8 μg/day, n = 5-6, P < 0.01). Olm treatment for 2 months reduced UAE, whereas Hyd treatment did not. Olm treatment reversed decreased gene and protein expressions of ACE2 and Mas receptor (Mas 1) in the kidney of Ren-TG mice and inhibited enhanced NADPH oxidase (Nox) 4 expression, whereas Hyd treatment had no influence. Furthermore, increased reactive oxygen species (ROS) in the kidney of Ren-TG mice were decreased by Olm treatment but not by Hyd treatment.
Olm treatment inhibits albuminuria and glomerular hypertrophy independently of blood pressure not only through its original AT1R blockade but also partly through the enhancement of the ACE2/Ang (1-7)/Mas axis and suppression of ROS generation.
