Sex Differences in Urinary Angiotensinogen (uAGT) Excretion, Renal Function, and Systolic Blood Pressure in 2‐Kidney, 1‐Clip Hypertensive Rats

Abstract

Intrarenal renin‐angiotensin system (RAS) activation and tissue injury in nonclipped kidneys of 2‐kidney, 1‐clip (2K1C) hypertensive rats have been characterized in previous studies of male but not female rats. To evaluate possible sex differences in response to renovascular hypertension, urinary angiotensinogen (uAGT) excretion, arterial blood pressure, urinary protein excretion, and renal function were assessed in 2K1C female rats.Female (n=8) and male (n=6) Sprague Dawley rats underwent placement of a 0.2 mm silver clip on the left renal artery to simulate unilateral renal artery stenosis. BP was measured by tail‐cuff plethysmography, and 24‐hour urine volume and water intake were monitored via metabolic cages over 21 days. After this period, renal clearance studies were conducted in anesthetized rats, and urine was collected from each kidney separately over 30 minute intervals. Urine protein concentration was determined by pyrogallol red method, and uAGT was measured by ELISA as an index of intrarenal RAS activity. Inulin and PAH concentrations were measured by spectrophotometry for calculation of glomerular filtration rate (GFR), renal plasma flow (RPF), and renal blood flow (RBF).21 days after renal artery clipping, systolic BP had risen to 176±8 mmHg from a baseline pressure of 120±1 mmHg, and urinary protein excretion increased to 20±5 mg/day in females. uAGT excretion was significantly increased from the baseline of 13 ng/day to 74 ng/day (507±127% increase). The nonclipped kidney showed 90±29% higher uAGT excretion compared to the clipped kidney, consistent with our previous findings in males. GFR and RPF were higher in nonclipped kidneys than in clipped kidneys but were greater than in corresponding measurements in males. GFR, RPF, and RBF were significantly higher in control rats compared to both clipped and nonclipped kidneys. Male rats showed significantly higher increases in uAGT, BP, and protein excretion.The present study demonstrates that BP, uAGT, and urinary protein excretion substantially increase after renal artery clipping in females, but the magnitude of the changes is markedly lower than in males. Additionally, the nonclipped kidney showed higher uAGT excretion compared to the clipped kidney. Although GFR, RPF, and RBF were significantly lower than control values for both clipped and nonclipped kidneys, these values were higher for females than males. These results demonstrated that female rats may be protected against AngII‐mediated renal injury and hypertension.Support or Funding InformationSupported by the ASPiRE Program at Tulane Univ Sch Medicine, New Orleans, LA and the Warren R. Bourgeois III, MD and Usha Ramadhyani Bourgeois, MD Student Research Endowed Fund at Tulane Univ Sch Medicine, New Orleans, LA