Simvastatin is Independently Improving Uremic Cardiomyopathy Through Intercommunication Between Macrophage and Cardiomyocyte in Renal Failure Model

Objective: Uremic cardiomyopathy (UC) is thought to be a significant cause of mortality in renal failure (RF). Several pharmacological interventions have been established for improving RF-induced cardiomyopathy. However, those drugs have not successfully treated the disease yet. Under uremic toxin conditions, the macrophage is able to polarise into M1 type pro-inflammatory and secreting pro-inflammatory factors into cardiomyocyte in RF.

Materials and methods: We analysed the effect of simvastatin on cardiac remodelling in the 5/6 nephrectomy (5/6 NX) uremic rat model in conjunction with the interaction of RAW 265.7 Macrophage and H9C2 cardiomyocyte cells in the cell culture system.

Results: Simvastatin failed to improve the RF phenotype. However, interestingly simvastatin prevented cardiac remodelling. Mechanistically, we found that simvastatin prevented uremic toxin-mediated M1 polarisation in macrophage cells, thus preventing the production of FGF-23 from macrophage, suggesting that simvastatin improved UC phenotype through ameliorating inflammation phenotype in macrophage. To identify the direct effect of pro-inflammatory macrophage secretome into cardiomyocytes, we incubated the H9C2 cardiomyocyte cell with the conditioned medium derived from RAW macrophage previously treated with indoxyl sulfate-induced uremic toxin/M1 stimulation and simvastatin. We showed that simvastatin prevented the enhancement of hypertrophy and fibrosis markers at mRNA levels in those H9C2 cells.

Conclusion: Our data highlight direct evidence of uremic toxin-mediated M1 macrophage and cardiomyocyte interaction to induce cardiac remodelling in RF through FGF-23 secretion and thus provides statin as a bonafide treatment for RF-induced cardiomyopathy.