In addition to the interaction with (P)RR, plasma prorenin/renin might directly contribute to cardiac remodeling and DCM-HF progression by non-enzymatically binding and activating the insulin-like growth factor II/mannose-6-phosphate (IGFII/M6P) receptor, which is highly expressed by cardiomyocytes and cardiac fibroblasts [75,109,124,125,126,127]. Here, REN is linked to familial dilated cardiomyopathy.