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Effects of Ovariectomy on Sex‐Dependent Differences in Hypertension and Renal Injury in 2‐Kidney 1‐Clip (2k1c) Goldblatt Hypertensive Rats

Previous studies demonstrated sex differences in hypertension in rats with unilateral renal artery stenosis (2K1C), with females developing a significantly lower degree of hypertension, urinary angiotensinogen (uAGT) and renal injury than males. The present study focused on the protective role estrogen may play in the development of hypertension by exploring the responses in 2K1C ovariectomized (OVX) female rats. A 0.2mm silver clip was placed on the left renal artery of OVX rats (n=4) with other rats left intact (n=4). Blood pressures (BP) of both groups were recorded on days ‐1, 3, 7, 14, and 21 using tail cuff plethysmography. Rats were placed in metabolic cages for 24 hours to measure water intake and urine volume. Rats were subjected to clearance studies on day 22. Following anesthesia with pentobarbital, the jugular vein was catheterized and infused with an inulin/PAH saline/albumin solution at a rate of 1.2mL/hour. A femoral artery catheter was used to continuously measure arterial pressure. The right and left ureters were catheterized, and urine flow was collected in 30min periods over 2 hours for uAGT ELISA and renal function analyses. Right and left kidneys were sectioned for RNA and histology to determine degree of kidney injury. BP in OVX 2K1C rats trended higher than BP in intact 2K1C females and were statistically higher by day 21. The OVX 2K1C rats did not show statistical differences in BP, urine volume, or uAGT compared to males. In OVX rats, clipped kidneys showed reduced kidney function as compared to intact 2K1C females, trending similar to male 2K1C data. Preliminary PAS data suggests that the degree of renal injury in OVX females is greater than in intact 2K1C females. In addition, nonclipped kidneys of OVX rats showed significantly greater uAGT excretion than the clipped kidneys, further supporting the role of intrarenal RAS in mediating hypertensive and renal injury responses in 2K1C rats. In conclusion, the increased uAGT in OVX rats indicate augmented intrarenal angiotensin II levels and are associated with decreased renal function in OVX rats vs. control and vs. intact 2K1C females. Our data suggests that removal of estrogen partially reduces its protective role against hypertension in females. Further tissue analysis will reveal the degree of renal injury. Our findings help explain sex‐differences in hypertension and suggest the need for further research specifically focused on treatment and management of hypertension in women.