Aged female rats with a history of recovery from AKI exhibit greater renal injury, fibrosis, and inflammation than aged shams

Acute kidney injury (AKI) is a significant risk factor for long-term cardiorenal complications, including chronic kidney disease (CKD). Despite AKI affecting both men and women and the prevalence of CKD being higher in women with age than in men, most AKI studies have used male rodent models. The mechanisms by which AKI predisposes females to adverse renal outcomes with aging remain poorly understood. Therefore, the goal of the current study was to test the hypothesis that a single episode of renal ischemia exacerbates age-related increases in renal injury, fibrosis, and inflammation vs. age-matched sham controls. 12-week-old female Sprague Dawley rats were randomized to either 45 minutes of bilateral renal ischemia-reperfusion as an experimental model of AKI or sham surgery (N=3-6/group). Rats were aged for 2 years. Rats were weighed, euthanized, and kidney and heart weights were recorded. One kidney was processed for flow cytometry to analyze immune cell profiles. The second kidney was used to measure renal injury, cellular stress, and fibrosis using histology and Western blot analysis. Aged AKI rats weighed less (304±29g vs. 356±9, p<0.05) and exhibited greater heart mass to body weight ratio (0.004±0.0005 vs. 0.003±0.0001, p<0.05) and greater kidney mass to body weight ratio (0.004±0.0004 vs. 0.003±0.0001, p<0.05) compared to aged sham rats. Histological scoring revealed greater tubular (p<0.05) and glomerular injury (p<0.05) and a greater urinary protein-to-creatinine ratio (34.7±4 U/mg/dl vs. 5.2±2, p<0.05) in aged AKI rats compared to aged sham rats. In addition to renal injury, aged AKI rats had greater fibrosis expression, evidenced by Masson’s trichrome (p<0.05) and vimentin staining (p<0.05) than aged shams. Aged AKI rats had greater levels of renal CD45+ (509214±109946 cells/kidney vs. 215512±32795, p<0.05), CD3+ (187990±26420 cells/kidney vs. 88632±18228, p<0.05), and CD4+ (100483±13063 cells/kidney vs. 26851±8770, p<0.05) T cells in addition to greater renal CD68+ macrophages (140±42 CD68+ positive cells per area vs. 19.6±1.4, p<0.05) than aged shams. Aged AKI rats also had greater protein expression of p-ERK/ERK (1.0±0.2 vs. 0.4±0.02, p<0.05), p-P38/GAPDH (0.7±0.1 vs. 0.3±0.04, p<0.05), and pJNK/GAPDH (0.8±0.1 vs. 0.4±0.1, p<0.05), along with lower levels of GPx4/GAPDH (0.7±0.2 vs. 1.4±0.07, p<0.05), suggesting greater cellular stress compared to aged sham rats. Additionally, aged AKI rats had greater phosphorylation of the pSTAT3/STAT3 pathway compared to aged sham controls, commonly linked to fibrosis and inflammation (1.0 ± 0.3 vs. 0.1 ± 0.1, P< 0.05). Taken together, these data suggest that a history of AKI in female rats exacerbates age-related changes in renal structure and function. Future studies are needed to explore the mechanisms by which an AKI history predisposes females to these adverse renal outcomes with aging. NIH-RO1DK134695 AHA-24PRE1196923 This abstract was presented at the American Physiology Summit 2025 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.