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Updated: Jul 17, 2025
A Mouse 5/6th Nephrectomy Model That Induces Experimental Uremic Cardiomyopathy
Published on: November 7, 2017
The kisspeptin-1 receptor antagonist peptide-234 aggravates uremic cardiomyopathy in a rat model
Hoa Dinh1,2, Zsuzsanna Z A Kovács1, Fanni Márványkövi1
1Department of Biochemistry and Interdisciplinary Centre of Excellence, Albert Szent-Györgyi Medical School, University of Szeged, 6720, Szeged, Hungary.
Insights
The kisspeptin receptor antagonist peptide-234 (P234) worsened uremic cardiomyopathy in rats. A higher dose of P234 accelerated cardiac fibrosis and remodeling, suggesting P234 activates fibrotic pathways.
Area of Science:
- Nephrology
- Cardiology
- Endocrinology
Background:
- Uremic cardiomyopathy involves diastolic dysfunction, left ventricular hypertrophy (LVH), and fibrosis.
- Kisspeptin receptor (KISS1R) pathways are implicated in fibrosis in cancer, but their role in uremic cardiomyopathy is unclear.
Purpose of the Study:
- To investigate the effects of the KISS1R antagonist peptide-234 (P234) on the development of uremic cardiomyopathy in a rat model.
Main Methods:
- Male Wistar rats underwent 5/6 nephrectomy to induce chronic kidney disease (CKD).
- CKD rats were treated with low (13 µg/day) or high (26 µg/day) doses of P234, or vehicle.
- Cardiac structure, fibrosis, and gene expression related to remodeling, stretch, and apoptosis were assessed.
Main Results:
- P234 did not affect kidney function markers (creatinine clearance, proteinuria).
- The higher dose of P234 significantly reduced cardiac wall thickness and increased interstitial fibrosis.
- Gene expression analysis revealed upregulation of remodeling, stretch, and apoptosis-related genes with higher P234 dose, indicating accelerated pathophysiology.
Conclusions:
- A higher dose of P234 exacerbates uremic cardiomyopathy by promoting cardiac fibrosis and remodeling.
- The findings suggest P234 activates fibrotic pathways, specifically TGF-β-mediated pathways, contributing to uremic cardiomyopathy progression.
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.
