The Kisspeptin-1 Receptor Antagonist Peptide-234 Aggravates Uremic Cardiomyopathy in a Rat Model

Dinh, Hoa and Kovács, Zsuzsanna Z. A. and Márványkövi, Fanni and Kis, Merse and Kupecz, Klaudia and Szűcs, Gergő and Freiwan, Marah and Siska, Andrea and Ibos, Katalin Eszter and Bodnár, Éva and Kriston, András and Kovács, Ferenc and Horváth, Péter and Földesi, Imre and Cserni, Gábor and Pokreisz, Péter and Kiss, Attila and Dux, László and Csabafi, Krisztina and Sárközy, Márta (2023) The Kisspeptin-1 Receptor Antagonist Peptide-234 Aggravates Uremic Cardiomyopathy in a Rat Model. SCIENTIFIC REPORTS, 13. No.-14046. ISSN 2045-2322

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Abstract

Uremic cardiomyopathy is characterized by diastolic dysfunction, left ventricular hypertrophy (LVH), and fibrosis. Dysregulation of the kisspeptin receptor (KISS1R)-mediated pathways are associated with the development of fibrosis in cancerous diseases. Here, we investigated the effects of the KISS1R antagonist peptide-234 (P234) on the development of uremic cardiomyopathy. Male Wistar rats (300–350 g) were randomized into four groups: (i) Sham, (ii) chronic kidney disease (CKD) induced by 5/6 nephrectomy, (iii) CKD treated with a lower dose of P234 ( ip. 13 µg/day), (iv) CKD treated with a higher dose of P234 ( ip. 26 µg/day). Treatments were administered daily from week 3 for 10 days. At week 13, the P234 administration did not influence the creatinine clearance and urinary protein excretion. However, the higher dose of P234 led to reduced anterior and posterior wall thicknesses, more severe interstitial fibrosis, and overexpression of genes associated with left ventricular remodeling ( Ctgf, Tgfb, Col3a1, Mmp9 ), stretch ( Nppa ), and apoptosis ( Bax, Bcl2, Casp7 ) compared to the CKD group. In contrast, no significant differences were found in the expressions of apoptosis-associated proteins between the groups. Our results suggest that the higher dose of P234 hastens the development and pathophysiology of uremic cardiomyopathy by activating the fibrotic TGF-β-mediated pathways.

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