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CB1 cannabinoid receptor antagonist attenuates left ventricular hypertrophy and Akt-mediated cardiac fibrosis in experimental uremia

      Highlights

      • CB1R inhibition attenuated LVH and Akt-mediated cardiac fibrosis in a CKD mice model.
      • The uremic toxin indoxyl sulfate stimulated CB1R and fibrotic marker expression.
      • CB1R inhibition caused anti-fibrotic effects via Akt signal modulation.
      • Drugs targeting CB1R may have therapeutic potential for uremic cardiomyopathy.

      Abstract

      Cannabinoid receptor type 1 (CB1R) plays an important role in the development of myocardial hypertrophy and fibrosis—2 pathological features of uremic cardiomyopathy. However, it remains unknown whether CB1R is involved in the pathogenesis of uremic cardiomyopathy. Here, we aimed to elucidate the role of CB1R in the development of uremic cardiomyopathy via modulation of Akt signalling. The heart size and myocardial fibrosis were evaluated by echocardiography and immunohistochemical staining, respectively, in 5/6 nephrectomy chronic kidney disease (CKD) mice treated with a CB1R antagonist. CB1R and fibrosis marker expression levels were determined by immunoblotting in H9c2 cells exposed to the uremic toxin indoxyl sulfate (IS), with an organic anion transporter 1 inhibitor or a CB1R antagonist or agonist. Akt phosphorylation was also assessed to examine the signaling pathways downstream of CB1R activation induced by IS in H9c2 cells. CKD mice exhibited marked left ventricular hypertrophy and myocardial fibrosis, which were reversed by treatment with the CB1R antagonist. CB1R, collagen I, transforming growth factor (TGF)-β, and α-smooth muscle actin (SMA) expression showed time- and dose-dependent upregulation in H9c2 cells treated with IS. The inhibition of CB1R by either CB1R antagonist or small interfering RNA-mediated knockdown attenuated the expression of collagen I, TGF-β, and α-SMA in IS-treated H9c2 cells, while Akt phosphorylation was enhanced by CB1R agonist and abrogated by CB1R antagonist in these cells. In summary, we conclude that CB1R blockade attenuates LVH and Akt-mediated cardiac fibrosis in a CKD mouse model. Uremic toxin IS stimulates the expression of CB1R and fibrotic markers and CB1R inhibition exerts anti-fibrotic effects via modulation of Akt signaling in H9c2 myofibroblasts. Therefore, the development of drugs targeting CB1R may have therapeutic potential in the treatment of uremic cardiomyopathy.

      Abbreviations:

      α-SMA (α-smooth muscle actin), ANP (atrial natriuretic peptide), β-MHC (myosin heavy chain beta), BNP (brain natriuretic peptide), BW (body weight), CB1R (cannabinoid receptor type 1), CKD (chronic kidney disease), CMR (cardiac magnetic resonance), CVD (cardiovascular disease), GAPDH (glyceraldehyde-3-phosphate dehydrogenase), HW (heart weight), IL (interleukin), IS (indoxyl sulfate), LVH (left ventricular hypertrophy), MAPK (mitogen-activated protein kinase), NF-κB (nuclear factor κB), PI3K (phosphoinositide-3-kinase protein kinase), PARP (poly ADP-ribose polymerase), PNx (partial nephrectomy), PtdIns (phosphatidylinositol), siRNA (short interfering RNA), TGF (transforming growth factor)

      Keywords

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