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

Jonathan W. Nelson, Alicia A. McDonough, Zhidan Xiang, Donna L. Ralph, Joshua A. Robertson, Jorge F. Giani, Kenneth E. Bernstein, Susan B. Gurley

Research output: Contribution to journalArticlepeer-review

Abstract

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 Naþ and volume balance. We aimed to determine how loss of angiotensin II signaling in the proximal tubule (PT), which reabsorbs the bulk of filtered Naþ and volume, impacts solute transport throughout the nephron. We hypothesized that PT renin-angiotensin system disruption would not only depress PT Naþ transporters but also impact downstream Naþ transporters. Using a mouse model in which the angiotensin type 1a receptor (AT1aR) is deleted specifically within the PT (AT1aR PTKO), we profiled the abundance of Naþ transporters, channels, and claudins along the nephron. Absence of PT AT1aR signaling was associated with lower abundance of PT transporters (Naþ/Hþ exchanger isoform 3, electrogenic Naþ-bicarbonate cotransporter 1, and claudin 2) as well as lower abundance of downstream transporters (total and phosphorylated Naþ-Kþ-2Cl- cotransporter, medullary Naþ-Kþ-ATPase, phosphorylated NaCl cotransporter, and claudin 7) versus controls. However, transport activities of Naþ-Kþ-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 Naþ reabsorption in the PT at baseline and the associated influence on downstream Naþ transporters, highlighting the ability of the nephron to integrate Naþ 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 Naþ transporters throughout the nephron, thereby contributing to the integrated control of fluid balance in vivo.

Original languageEnglish (US)
Pages (from-to)F69-F81
JournalAmerican Journal of Physiology - Renal Physiology
Volume321
Issue number1
DOIs
StatePublished - Jul 2021

Keywords

  • Angiotensin receptor
  • Nephron
  • Proximal tubule
  • Transporters

ASJC Scopus subject areas

  • Physiology
  • Urology

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