Local and downstream actions of proximal tubule angiotensin II signaling on Na ^þ transporters in the mouse nephron

The renal nephron consists of a series of distinct cell types that function in concert to maintain fluid and electrolyte balance and blood pressure. The renin-angiotensin system (RAS) is central to Na^þ and volume balance. We aimed to determine how loss of angiotensin II signaling in the proximal tubule (PT), which reabsorbs the bulk of filtered Na^þ and volume, impacts solute transport throughout the nephron. We hypothesized that PT renin-angiotensin system disruption would not only depress PT Na^þ transporters but also impact downstream Na^þ transporters. Using a mouse model in which the angiotensin type 1a receptor (AT_1aR) is deleted specifically within the PT (AT_1aR PTKO), we profiled the abundance of Na^þ transporters, channels, and claudins along the nephron. Absence of PT AT_1aR signaling was associated with lower abundance of PT transporters (Na^þ/H^þ exchanger isoform 3, electrogenic Na^þ-bicarbonate cotransporter 1, and claudin 2) as well as lower abundance of downstream transporters (total and phosphorylated Na^þ-K^þ-2Cl- cotransporter, medullary Na^þ-K^þ-ATPase, phosphorylated NaCl cotransporter, and claudin 7) versus controls. However, transport activities of Na^þ-K^þ-2Cl- cotransporter and NaCl cotransporter (assessed with diuretics) were similar between groups in order to maintain electrolyte balance. Together, these results demonstrate the primary impact of angiotensin II regulation on Na^þ reabsorption in the PT at baseline and the associated influence on downstream Na^þ transporters, highlighting the ability of the nephron to integrate Na^þ transport along the nephron to maintain homeostasis. NEW & NOTEWORTHY Our study defines a novel role for proximal tubule angiotensin receptors in regulating the abundance of Na^þ transporters throughout the nephron, thereby contributing to the integrated control of fluid balance in vivo.