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Left ventricular hypertrophy in experimental chronic kidney disease is associated with reduced expression of cardiac
Sheila K Patel1, Elena Velkoska2, Daniel Gayed2
1Department of Medicine, Austin Health, The University of Melbourne, Level 7 Lance Townsend Building, Austin Hospital, 145 Studley Road, Heidelberg, VIC, 3084, Australia. skpatel@unimelb.edu.au.
Insights
Chronic kidney disease (CKD) causes left ventricular hypertrophy (LVH) by reducing Kruppel-like factor 15 (KLF15). Angiotensin converting enzyme (ACE) inhibition restores KLF15 levels, mitigating LVH and fibrosis in CKD.
Area of Science:
- Cardiovascular Medicine
- Nephrology
- Molecular Biology
Background:
- Left ventricular hypertrophy (LVH) is a significant risk factor for mortality in patients with chronic kidney disease (CKD).
- Kruppel-like factor 15 (KLF15) is a cardiac transcription factor known to inhibit cardiac hypertrophy and fibrosis.
- The role of KLF15 in CKD-induced LVH and the effect of angiotensin converting enzyme (ACE) inhibition on its expression remain unclear.
Purpose of the Study:
- To investigate changes in cardiac KLF15 expression in a rat model of CKD-induced LVH.
- To determine if ACE inhibition can modulate KLF15 expression and ameliorate cardiac remodeling in this model.
Main Methods:
- Chronic kidney disease (CKD) was induced in rats via subtotal nephrectomy (STNx).
- Rats were treated with either vehicle or ramipril (an ACE inhibitor) for four weeks.
- Cardiac structure, function, and KLF15 expression (mRNA and protein) were assessed.
Main Results:
- STNx induced significant kidney dysfunction, hypertension, LVH, and cardiac fibrosis.
- Cardiac KLF15 mRNA and protein levels were significantly reduced in STNx rats, accompanied by increased expression of hypertrophic markers (ANP, BNP) and CTGF.
- Ramipril treatment effectively reduced blood pressure, LVH, and fibrosis, and importantly, increased cardiac KLF15 expression, leading to decreased expression of hypertrophic markers and CTGF.
Conclusions:
- Loss of cardiac KLF15 is associated with increased trophic and fibrotic signaling in CKD-induced LVH.
- ACE inhibition demonstrates a protective effect by ameliorating cardiac remodeling and restoring cardiac KLF15 levels in CKD.
Background:
Left ventricular hypertrophy (LVH) increases the risk of death in chronic kidney disease (CKD). The transcription factor Kruppel-like factor 15 (KLF15) is expressed in the heart and regulates cardiac remodelling through inhibition of hypertrophy and fibrosis. It is unknown if KLF15 expression is changed in CKD induced LVH, or whether expression is modulated by blood pressure reduction using angiotensin converting enzyme (ACE) inhibition.
Methods:
CKD was induced in Sprague-Dawley rats by subtotal nephrectomy (STNx), and rats received vehicle (n = 10) or ACE inhibition (ramipril, 1 mg/kg/day, n = 10) for 4 weeks. Control, sham-operated rats (n = 9) received vehicle. Cardiac structure and function and expression of KLF15 were assessed.
Results:
STNx caused impaired kidney function (P < 0.001), hypertension (P < 0.01), LVH (P < 0.001) and fibrosis (P < 0.05). LVH was associated with increased gene expression of hypertrophic markers, atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP, P < 0.01) and connective tissue growth factor (CTGF) (P < 0.05). Cardiac KLF15 mRNA and protein expression were reduced (P < 0.05) in STNx and levels of the transcription regulator, GATA binding protein 4 were increased (P < 0.05). Ramipril reduced blood pressure (P < 0.001), LVH (P < 0.001) and fibrosis (P < 0.05), and increased cardiac KLF15 gene (P < 0.05) and protein levels (P < 0.01). This was associated with reduced ANP, BNP and CTGF mRNA (all P < 0.05).
Conclusion:
This is the first evidence that loss of cardiac KLF15 in CKD induced LVH is associated with unchecked trophic and fibrotic signalling, and that ACE inhibition ameliorates loss of cardiac KLF15.
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