Sex Differences in a Preclinical Model of Type II Cardiorenal Syndrome with Loop Diuretic Resistance

Cardiorenal syndrome-II (CRS-II) encompasses concurrent kidney disease secondary to chronic heart failure (HF). Almost 50% of cases of myocardial infarction (MI) progress to HF with the eventual development of chronic kidney disease. Most patients with CRS-II develop edema, which is mainly treated with loop diuretics that inhibit the apical Na/K/2Cl cotransporter, NKCC2, in the thick ascending limb (TAL). However, in nearly 50% of HF patients the response to loop diuretics is diminished and eventually become resistant. Sex differences in glomerular function and loop diuretic resistance in CRS-II are poorly characterized in the literature. Few studies have used the mouse as a model of CRS-II after myocardial infarction (MI) due to its innate resistance to renal damage. We previously showed that male C57BL/6J mice with induced HF (LAD ligation) have reduced glomerular filtration rate (GFR) post MI, and have an attenuated response to loop diuretics, indicative of loop diuretic resistance. We hypothesize that female C57BL/6J mice would be somewhat protected from kidney damage and loop diuretic resistance after MI. Heart failure was induced in 12-week-old male and female C57BL/6J mice through ligation of the left anterior descending coronary artery (LAD), classified as MI group, and compared to a sham surgery group (without ligation). Both groups were assessed for heart function by echocardiography and glomerular filtration rate (FITC inulin) in conscious mice. The response to diuretics was studied in metabolic cages. Male and female MI mice had over 50% reduction in ejection fraction (EF) 3 months after MI compared to sham group (Male MI: 30.3 ± 1.9%, Sham: 73.1 ± 0.2%; Female MI: 35.8±2.2%, Sham: 73.8±1.6%, n= 8 each group, p<0.05 MI vs sham). EF continued to be lower 6 months after MI. Cardiac index was decreased in both male and female MI mice (Male MI: 6.9 ± 0.4, Sham: 9.8 ± 0.4; Female MI: 8.7 ± 0.5, Sham: 10.3 ± 0.6, n= 10 each group, p<0.05 MI vs sham). Male mice showed lower GFR 6 months post MI. However, female MI mice showed unchanged GFR 6 months after MI (Male MI: 0.5 ± 0.1, Sham: 0.8±0.1 µl/min, p<0.05; Female MI:1.4 ± 0.2, Sham:1.3±0.2, n=5 MI, n=6 sham). In metabolic cage studies, after a saturating dose of the NKCC2 inhibitor bumetanide (20 mg/Kg), male MI mice had attenuated diuresis and natriuresis compared to sham mice (Male MI ∆UV: 0.9±0.2 ml/4h, ∆UNa: 65.0 ± 4.5 µmols/4h, n= 4; Male sham ∆UV: 2.0±0.3 ml/4h, ∆UNa: 117.2±11.0 µmols/4h, n= 6, p<0.05 vs sham). However, in female mice, the response to bumetanide was similar between groups (Female MI ∆UV: 1.1±0.1 ml/4h, ∆UNa: 99.6±14.6µmols/4h, n= 9; Female Sham ∆UV: 1.0±0.1 ml/4h, ∆UNa: 66.6±13.4µmols/4h, n= 6, p>0.05 vs sham). Our data suggests that the kidneys in females are largely protected, with unchanged GFR, despite developing heart failure with low ejection fraction post MI. Female mice did not develop loop diuretic resistance post-MI whereas male mice did. We conclude that in C57BL/6J mice, decreased renal filtration function and response to loop diuretics in MI-induced heart failure only occurs in males whereas females are largely protected. 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.