Differential Myocardial Responses in Male and Female Rats with Uremic Cardiomyopathy

Bódi, Beáta and Vágó, Rebeka Rita and Nagy, László and Ráduly, Arnold Péter and Gulyás, András and Kupecz, Klaudia and Azar, Lilian and Márványkövi, Fanni Magdolna and Szűcs, Gergő and Siska, Andrea and Cserni, Gábor and Földesi, Imre and Papp, Zoltán and Sárközy, Márta (2025) Differential Myocardial Responses in Male and Female Rats with Uremic Cardiomyopathy. INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, 26 (5). No. 2259. ISSN 1661-6596

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Abstract

Uremic cardiomyopathy, characterized by diastolic dysfunction, left ventricular hypertrophy (LVH), and fibrosis, is a common cardiovascular complication of chronic kidney disease (CKD). Men are at a higher risk for cardiovascular and renal diseases, compared to age-matched, pre-menopausal women. We aimed to investigate the influence of sex on the severity of uremic cardiomyopathy through the characterization of functional and molecular indices of myocardial remodeling in a rat model. CKD was induced by a 5/6 nephrectomy in 9-week-old male and female Wistar rats. Serum and urine tests, transthoracic echocardiography, left ventricular (LV) histology, and quantitative reverse transcription polymerase chain reaction (RT-qPCR) were performed at week 8 or 9. Moreover, LV alterations were also tested in permeabilized cardiomyocytes (CMs) by force measurements and Western immunoblotting. CKD resulted in the development of a more severe uremic cardiomyopathy in male rats—including LVH, LV diastolic dysfunction, and fibrosis—than in female rats, where only LVH was observed. A uremic cardiomyopathy was also associated with a decrease in maximal Ca2+-activated force (Fmax) in CMs of male rats. Additionally, increases in CM Ca2+-independent passive stiffness (Fpassive) and decreases in cardiac myosin-binding protein C (cMyBP-C) phosphorylation levels were significantly larger in male than female rats. In conclusion, a uremic cardiomyopathy involved cardiac remodeling in both sexes. Nevertheless, male rats exhibited more pronounced signs of macroscopic and microscopic alterations than their female counterparts, illustrating a sex-dependent component of uremic cardiomyopathy.

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