Insight into the mechanism underlying TZD chronic reduction of arterial pressure may be derived 1) through the effects of TZD on the activity of NCC, the renal target for TZD diuresis (Table 1e), and the relationship between NCC activity and arterial pressure in responders and nonresponders; 2) in NCC knockout and NCC/pendrin double-knockout mice (Schultheis et al., 1998; Loffing et al., 2004; Soleimani et al., 2012; Alshahrani et al., 2017a); and 3) in humans with dysfunctional NCC, i.e., Gitelman’s syndrome (Table 1l);. The gene discussed is SLC12A3; the disease is Gitelman syndrome.