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 la 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 NaCI cotransporter, and claudin 7) versus controls. However, transport activities of Na+-K+-2Cl(-) cotransporter and NaCI 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.

Automated summary

The study identifies a novel role for proximal tubule angiotensin receptors in regulating the abundance of Na+ transporters throughout the nephron, contributing to the integrated control of fluid balance in vivo.