AGT and diabetic kidney disease: 2006; Wu et al. 2014). The combination of high glucose and high levels of Ang II achieved a higher level of APJ and preproapelin downregulation than the high glucose environment alone (Fig. 8). This synergistic effect may explain the low level of APJ observed in the db/db mouse model of DKD where we found that the RAS is overactive at the kidney level (i.e., increased urinary AOG and Ang II). Overactivity of the kidney RAS is a feature of other models of DKD and human DKD (Tamura et al. 2005; Peti‐Peterdi et al. 2008; Umemoto et al. 2016; Wysocki et al. 2017a,b; Patney et al. 2018).