GPER‐1 activation reduces oxidative stress and alters renin‐angiotensin system components in the kidneys of salt‐sensitive mRen2.Lewis females

Abstract

Female mRen2.Lewis (mRen2) rats fed a high salt diet (HS) exhibit increased blood pressure and end organ injury, as well as enhanced renal expression of the novel estrogen receptor GPER‐1 (GPR30). We reported that in vivo activation of GPER‐1 by the agonist G‐1 did not alter blood pressure in HS females; however, renal hypertrophy and proteinuria were reduced and creatinine clearance was increased. The current study examined the mechanisms that may contribute to the protective actions of G‐1 in the HS fed female mRen2. Urinary excretion of norepinephrine, epinephrine, sodium, and potassium were not altered by G‐1. However, urinary excretion of 8‐isoprostane was decreased by G‐1 (4.8 ± 0.3 vs. 2.8 ± 0.4 ng/mg creatinine, N=9 per group, P<0.01). In addition, 4‐hydroxy‐2‐nonenal (4‐HNE) staining, another marker of oxidative stress, was decreased with G‐1 (P<0.05, N=4 per group). While renal ACE activity was unchanged, G‐1 increased ACE2 activity (18 ± 1 vs. 23 ± 1 fmol/mg/min, N=4 per group, P<0.05) and decreased neprilysin activity (1526±74 vs. 1223±56 fmol/mg/min, N=4 per group, P<0.05). Finally, G‐1 treatment reduced mRNA levels of cortical angiotensinogen by 70% (N=7–8, P<0.01). We conclude that the renoprotective actions of GPER‐1 activation may involve attenuation of oxidative stress and differential regulation of the renin‐angiotensin system within the kidney. Funding: HL‐56973, HL‐51952, AHA 0825515.