Aromatase is a monooxygenase that catalyzes the rate-limiting step of estrogen biosynthesis from androgens. Aromatase inhibitors are widely used for the treatment of patients with hormone receptor-positive breast cancer. However, the effects of aromatase inhibitors on cardiovascular and renal health in females are understudied. Given that estrogen is protective against cardiovascular and kidney diseases, we hypothesized that aromatase inhibition elevates blood pressure and induces kidney injury in female Sprague–Dawley rats. Twelve-week-old female rats were implanted with radiotelemetry transmitters to continuously monitor blood pressure. After baseline blood pressure recording, rats were randomly assigned to treatment with the aromatase inhibitor anastrozole (ASZ) or vehicle (Veh) in drinking water. Twenty days after treatment initiation, rats were shifted from a normal-salt (NS) diet to a high-salt (HS) diet for an additional 40 days. Rats were euthanized 60 days after treatment initiation. Body weight increased in both groups over the study period, but the increase was greater in the ASZ-treated group than in the Veh-treated group. Mean arterial pressure increased in ASZ-treated rats during the NS and HS diet phases but remained unchanged in Veh-treated rats. In addition, urinary excretion of albumin and kidney injury marker-1 and plasma urea were increased in response to aromatase inhibition. Furthermore, histological assessment revealed that ASZ treatment increased morphological evidence of renal tubular injury and proximal tubular brush border loss. In conclusion, chronic aromatase inhibition in vivo with ASZ increases blood pressure and markers of renal proximal tubular injury in female Sprague–Dawley rats, suggesting an important role for aromatization in the maintenance cardiovascular and renal health in females.
Bibliographical noteFunding Information:
This work was supported by the National Institute of Diabetes and Digestive and Kidney Diseases Grant K99/R00DK119413 (to E.Y.G.), the University of Alabama at Birmingham Hypertension Research Center, and the O’Brien Kidney Research Center.
We appreciate Maryam K. Butt and Dr. Xiaofen Liu’s outstanding assistance with immunohistochemistry experiments. We thank Ginger Guthrie and Dr. Chunhua Jin for the technical assistance. We value the help of Dr. Celso Gomez-Sanchez and Dr. Elise Gomez-Sanchez with aldosterone assays. We appreciate support from the University of Alabama at Birmingham/ Universtiy of California-San Diego O’Brien Core Center for Acute Kidney Injury Research for creatinine measurements and the Vanderbilt Biostatistics Clinic for the biostatistics consultation. We are grateful to Dr. Carmen De Miguel for valuable suggestions. The graphical abstract was created with BioRender.com.
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- dietary sodium
- proximal tubule