ACE and Hypertension: This may be due to several factors, including, but not limited to, (a) the expression of the substrate angiotensinogen and key enzymes renin and ACE for the generation of Ang II onsite; (b) the capacity of AT1 (AT1a) receptor- and the endocytic receptor megalin-mediated accumulation of circulating and tissue paracrine Ang II by the proximal tubules [88,89,90]; and (c) the feedforward regulatory mechanisms of intratubular RAS in the proximal tubules during the development of Ang II-induced hypertension [87,91].