Shen-Shuai-Ⅱ Recipe ameliorates chronic kidney disease-induced myocardial injury via inhibition of the IL-18/IL-18R1/MyD88 pathway.

BACKGROUND

Chronic kidney disease (CKD) is a significant risk factor for myocardial injury. Despite the proven clinical safety and efficacy of Shen Shuai II Recipe (SSR) in CKD management, and evidence of its renoprotective effects involving anti-inflammation and mitochondrial protection in experimental models, its potential to ameliorate CKD-related myocardial injury has not been investigated.

PURPOSE: We sought to determine whether SSR confers protection against CKD-induced myocardial injury by suppressing the IL-18/IL-18R1/MyD88 pathway.

METHODS

A CKD model was established in rats by 5/6 (A/I) surgery. The rats were randomly assigned to receive daily gavage of normal saline, SSR, or Losartan potassium for 8 weeks. In vitro, IL-18-stimulated H9C2 cells were treated with different concentrations of SSR, or H9C2 cells were directly treated with different concentrations of 5/6 (A/I)+SSR rat serum. The effects of SSR and rat serum on the IL-18R1/MyD88-mediated inflammatory pathway and myocardial injury were investigated via immunoblotting, luminex chip assay, histopathology and fluorescence staining. Additionally, to further elucidate the mechanisms of SSR against myocardial injury, H9C2 cells were treated with 5/6 (A/I) or 5/6 (A/I)+SSR rat serum in the presence or absence of IL-18 neutralizing antibody. Next, we delivered IL-18R1 overexpression plasmid or MyD88 inhibitor into the IL-18-treated H9C2 cells with concomitant SSR administration. Finally, using a co-culture approach, we explored whether hypoxic renal tubular cells induced myocardial injury via the IL-18R1/MyD88 pathway.

RESULTS

SSR inhibited IL-18R1/MyD88-mediated inflammatory response, decreased the expression of β-MHC and ANP hypertrophy marker proteins, and attenuated myocardial injury in myocardial tissues of 5/6 (A/I) rats or IL-18-treated H9C2 cells. The same effect was also observed in H9C2 cells treated with 5/6 (A/I)+SSR rat serum. Further investigation confirmed that SSR ameliorated myocardial injury through suppression of the IL-18R1/MyD88 inflammatory pathway. More crucially, co-culture experiments demonstrated that SSR alleviated crosstalk between hypoxic tubular cells and cardiomyocytes via IL-18/IL-18R1/MyD88 pathway, thereby mitigating myocardial injury.

CONCLUSION

SSR ameliorates CKD-induced myocardial injury through suppression of the IL-18/IL-18R1/MyD88 pathway.