Heart rhythm disturbances have been widely recognized as major triggers of cardiovascular (CV) mortality in chronic kidney disease (CKD) patients. Connexin 43 (Cx43)-composed gap junctions are essential in cardiomyocyte synchronization and may be involved in the pathological response to uremic toxins. Indoxyl sulfate (IS) is one of the most dominant uremic toxins that contribute to CKD-related cardiovascular diseases. In primary cultures of rat neonatal cardiomyocytes, we demonstrated that IS treatment decreased spontaneous contraction without impairing viability. In addition, there was disruption of gap junction intercellular communication (GJIC) between cardiomyocytes after 30 min of IS stimulation. IS caused time- and dose-dependent Cx43 redistribution, and the patterns of Cx43 immunostaining returned to baseline while IS stimulation was removed. Furthermore, IS exposure downregulated Cx43 protein and mRNA levels. Elevated JNK1 and JNK2 phosphorylation was further identified after IS exposure in both rat cardiomyocytes and H9c2 cells. The above changes as well as GJIC and Cx43 suppression were reversed by pretreatment with a JNK inhibitor (SP600125). Inhibition of p-JNK attenuated IS-mediated downward trends in Cx43 transcription and translation. In cardiac muscle from nephrectomy-induced CKD mice, an alteration in Cx43 level was identified at intercalated discs. Our findings disclosed that JNK activation might participate in the remodeling of gap junction and Cx43 expression by uremic toxin-IS both in vitro and in vivo.
Keywords: Cardiomyocytes; Chronic kidney disease; Connexin 43; Indoxyl sulfate; JNK.
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