Abstract
Chronic heart failure (HF) frequently causes progressive decline in kidney function, known as cardiorenal syndrome-2 (CRS2). Current treatment options for CRS2 remain unacceptably limited. Trimethylamine-N-oxide (TMAO), a metabolite of gut microbiota, has recently been implicated in the pathogenesis of both HF and chronic kidney disease. Here we examined whether circulating TMAO is elevated in CRS2 and if so, whether attenuation of circulating TMAO would ameliorate the progression of CRS2. Sprague-Dawley rats underwent surgery for myocardial infarction (MI) or sham (week 0) followed by subtotal (5/6) nephrectomy (STNx) or sham at week 4 to induce CRS2 or control. At week 6, MI + STNx rats and control rats received vehicle or 1.0% 3,3-Dimethyl-1-butanol (DMB, a TMAO inhibitor) treatment for 8 weeks. Compared with control rats, MI + STNx rats exhibited elevated serum TMAO at week 6, which was increased further at week 14 but was attenuated by DMB treatment. MI + STNx rats showed cardiac dysfunction as assessed by echocardiography and renal dysfunction as evidenced by increased serum creatinine and urinary kidney injury molecule-1 and decreased creatinine clearance at week 6. The cardiac and renal dysfunction in MI + STNx rats was exacerbated at week 14 but was prevented by DMB treatment. Molecular and histological studies revealed myocyte hypertrophy and increases in interstitial myocardial fibrosis and gene expression of pro-hypertrophic and pro-fibrotic markers in both heart and kidney at week 14, which were accompanied by elevated gene expression of proinflammatory cytokines. The changes in molecular and histological parameters observed in MI + STNx rats were significantly reduced by DMB treatment. These findings suggest that rats with CRS2 have elevated circulating TMAO, which is associated with the exacerbation of cardiac and renal dysfunction. Attenuation of circulating TMAO can ameliorate cardiac and renal injury and prevents the progression of CRS2.
Highlights
Heart failure (HF) is a growing health problem and a major cause of mortality and morbidity in the world
The major findings of this study are: 1) Rats with cardiorenal syndrome type 2 (CRS2) exhibit elevated levels of circulating TMAO, which can be attenuated by treatment with TMAO inhibitor DMB; 2) Cardiac and renal dysfunction in rats with CRS2 are ameliorated after DMB treatment; 3) DMB treatment improves myocyte hypertrophy as well as cardiac and renal fibrosis in rats with CRS2; 4) DMB treatment reduces expression of proinflammatory cytokines in the heart and kidney in rats with CRS2
We found that myocardial infarction (MI) + STNx rats, compared with SHAM + SHAM controls, had significant higher levels of serum TMAO at week 6, which provides the direct evidence that circulating TMAO levels are elevated in CRS2
Summary
Heart failure (HF) is a growing health problem and a major cause of mortality and morbidity in the world. Patients with HF frequently develop secondary kidney impairment, resulting in a vicious cycle that exaggerates the decline in both cardiac and renal function. Kidney impairment arising from a primary defect in the heart has been defined as cardiorenal syndrome type 2 (CRS2) (Ronco et al, 2008; Savira et al, 2020a). Clinical studies have shown that even a slight worsening of renal function in patients with HF is associated with increased mortality and prolonged hospitalization (Gottlieb et al, 2002). Due to the dual impairment of the heart and the kidney in CRS2, definitive therapeutic options remain suboptimal and often empirical as no evidence-based treatment guidelines currently exist (Ronco et al, 2010; Muhlberger et al, 2012). Understanding the precise mechanisms and pharmacologically targeting a common pathway involved in both cardiac and renal pathophysiology may be a promising strategy in the CRS2 setting
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