Effects of proximal tubule-specific ATRAP enhancement on hypertension in a remnant kidney chronic kidney disease model of mice.

Chronic kidney disease (CKD) frequently accompanies hypertension, exacerbating CKD progression in a vicious cycle. Angiotensin II type 1 receptor-associated protein (ATRAP) promotes AT1 receptor internalization to inhibit hyperactivation of its downstream signaling. We previously reported that the downregulation of renal ATRAP expression had a critical role in the development of hypertension in a remnant kidney CKD model, through activation of epithelial sodium channel (ENaC) pathway. Although the distal-tubule was highlighted in CKD-related hypertension, the proximal tubule's role remained unclear. We generated proximal tubule-specific ATRAP transgenic (PT-ATRAP Tg) mice under the control of the Npt2 promoter and compared the effects of 5/6 nephrectomy (Nx) on blood pressure (BP) with those in littermate control (LC) wild-type mice. Immunohistochemical and laser microdissection analyses revealed that the proximal tubule-specific overexpression of ATRAP in PT-ATRAP Tg mice resulted in approximately 15-fold increase in ATRAP mRNA expression in the proximal tubules compared to LC mice. There were no significant differences in body weight, systolic BP, heart rate, and renal function between PT-ATRAP Tg and LC mice at baseline before surgery. Furthermore, twelve weeks after surgery, both PT-ATRAP Tg and LC mice that underwent 5/6 nephrectomy showed a similar increase in systolic BP compared to sham-operated mice, with no significant differences. Additionally, 5/6 Nx elevated renal ENaCα expression similarly in both groups. In conclusion, increased ATRAP expression in the proximal tubules does not affect hypertension in the remnant kidney CKD model, suggesting a pathological significance of distal tubules in this disease model.