Female Mouse Model of Vascular Dysfunction in Postmenopausal Chronic Kidney Disease

Cardiovascular disease (CVD) is the leading cause of death in patients with chronic kidney disease (CKD). Women with CKD are at particularly high CVD risk due to the combined detrimental effects of impaired kidney function and ovarian hormone loss. However, much of the clinical nephrology literature focuses on men, and studies on vascular health in women remain especially limited. This gap is further exacerbated by the absence of a preclinical animal model to study the effects of CKD superimposed on menopause on CVD risk. Therefore, the objective of this study was to establish a female murine model of vascular dysfunction resulting from postmenopausal CKD. We hypothesized that the postmenopausal CKD mouse model would display the most pronounced reductions in kidney and vascular function. Female C57Bl/6J mice (n=9-10/group; 12 weeks old) received 4-vinylcyclohexene diepoxide (VCD; 160 mg/kg body weight; Intraperitoneal IP injection for 20 consecutive days) to induce menopause via gradual ovarian follicle depletion. Postmenopausal status was confirmed by 10 consecutive days in diestrus. At 16 weeks of age, mice were administered aristolochic acid (AA; 3.5 mg/kg body weight; IP injection 3 times/week for 3 weeks, followed by 1 time/week for 3 weeks total 12 doses) to induce CKD through proximal tubule injury. The four groups were: (1) premenopausal control (Sesame oil vehicle+ phosphate buffered saline PBS; vehicle), (2) premenopausal CKD (Sesame oil+AA), (3) postmenopausal control (VCD+PBS), and (4) postmenopausal CKD (VCD+AA). Transcutaneous glomerular filtration rate (tGFR; a measure of kidney function) was assessed before VCD and at 4, 8, 12, 16, and 20 weeks post-AA. Aortic pulse wave velocity (PWV; the gold-standard measure of arterial stiffness) was assessed before VCD and at 12, 16, and 20 weeks post-AA. Endothelium-dependent dilation (EDD) to increasing doses of acetylcholine was evaluated in isolated carotid arteries at euthanasia, and peak dilatory responses are presented. Declines in tGFR were evident in our postmenopausal CKD model (VCD+AA) starting 8 weeks post-AA. By 20 weeks post-AA, there was a clear stepwise decline, with the lowest value in the postmenopausal CKD model (mean±s.d 135±26 μL/min), followed by premenopausal CKD (190±41), postmenopausal control (241±77), and the highest in premenopausal control (306±99) (ANOVA P< 0.001). Aortic PWV in postmenopausal CKD began to increase at 12 weeks post-AA and, by 20 weeks, followed a stepwise pattern: the greatest value was observed in postmenopausal CKD model (413±10 cm/sec), intermediate values in premenopausal CKD (403±18) and postmenopausal control (381±18), and the lowest in premenopausal control (380±10) (ANOVA P< 0.001). Peak EDD showed a modest stepwise reduction, with the lowest value in the postmenopausal CKD model (91±4 %), followed by premenopausal CKD (94±3) and postmenopausal control (96±2), and the highest in premenopausal control (98±3) (ANOVA P < 0.001). Our female murine model of postmenopausal CKD exhibited reduced kidney function and increased aortic stiffness. While endothelial function was statistically reduced, the magnitude of the impairment was modest and its physiological significance remains unclear. This model offers a strong platform for studying aortic stiffness in postmenopausal CKD. Future studies should evaluate whether different timing or duration of ovarian failure and CKD induction leads to more pronounced endothelial dysfunction. Support was provided by CU Anschutz SCORE on Sex Differences Pilot Grant (to ESO); CU Anschutz Ludeman Center Women's Health Innovation Scholar Award (to ESO); and CU Anschutz CCTSI Translational Methods Pilot Grant (to VEB). This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.