Local and downstream actions of proximal tubule angiotensin II signaling on Na+ 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 + 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 + and volume, impacts solute transport throughout the nephron. We hypothesized that PT renin-angiotensin system disruption would not only depress PT Na + transporters but also impact downstream Na + transporters. Using a mouse model in which the angiotensin type 1a receptor (AT 1a R) is deleted specifically within the PT (AT 1a R PTKO), we profiled the abundance of Na + transporters, channels, and claudins along the nephron. Absence of PT AT 1a R signaling was associated with lower abundance of PT transporters (Na + /H + exchanger isoform 3, electrogenic Na + -bicarbonate cotransporter 1, and claudin 2) as well as lower abundance of downstream transporters (total and phosphorylated Na + -K + -2Cl - cotransporter, medullary Na + -K + -ATPase, phosphorylated NaCl cotransporter, and claudin 7) versus controls. However, transport activities of Na + -K + -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 + reabsorption in the PT at baseline and the associated influence on downstream Na + transporters, highlighting the ability of the nephron to integrate Na + 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 + transporters throughout the nephron, thereby contributing to the integrated control of fluid balance in vivo.