The role of the complement factor B-arginase-polyamine molecular axis in uremia-induced cardiac remodeling in mice.

The role of complement system in heart diseases is controversial. Besides, the mechanisms by which complement components participate in cardiac remodeling (CR) and heart failure during uremia are unclear. In this study, 5/6 nephrectomy was performed to adult mice to establish the uremic model and CR deteriorated over the course of uremia. Although complement pathways were not further activated over the course of the disease, soluble complement factor B (CFB) was upregulated at post-nephrectomy day 90 (PNx90) compared with PNx30. Further, CFB notably deteriorated CR in uremic mice but this effect was reversed by depletion of macrophages with liposomal clodronate. In vivo and in vitro CFB upregulated arginase 1 (ARG1) expression, increased ARG1 enzymatic activity, and stimulated the syntheses of ornithine, leading to polyamine overproduction in macrophages. Putrescine, an important polyamine, promoted cardiac fibroblast proliferation and collagen production, resulting in progressive CR. In vivo the inhibition of ARG1 activity with Nω -hydroxyl-l-arginine remarkably improved the general survival rates, inhibited the infiltration of cardiac fibroblasts, and alleviated progression of CR in uremic mice. Taken together, the CFB-ARG1-putrescine axis is related to progression of CR and ARG1 hyperactivity in macrophages may provide a novel therapeutic target against the heart injury in uremia.