Dose-dependent effects of angiotensin-(1-7) on the NHE3 exchanger and [Ca(2+)](i) in in vivo proximal tubules

Am J Physiol Renal Physiol. 2013 May 15;304(10):F1258-65. doi: 10.1152/ajprenal.00401.2012. Epub 2013 Mar 20.


The acute direct action of angiotensin-(1-7) [ANG-(1-7)] on bicarbonate reabsorption (JHCO(3)(-)) was evaluated by stationary microperfusions on in vivo middle proximal tubules in rats using H ion-sensitive microelectrodes. The control JHCO(3)(-) is 2.82 ± 0.078 nmol·cm(-2)·s(-1) (50). ANG-(1-7) (10(-12) or 10(-9) M) in luminally perfused tubules decreases JHCO(3)(-) (36 or 60%, respectively), but ANG-(1-7) (10(-6) M) increases it (80%). A779 increases JHCO(3)(-) (30%) and prevents both the inhibitory and the stimulatory effects of ANG-(1-7) on it. S3226 decreases JHCO(3)(-) (45%) and changes the stimulatory effect of ANG-(1-7) to an inhibitory effect (30%) but does not affect the inhibitory effect of ANG-(1-7). Our results indicate that in the basal condition endogenous ANG-(1-7) inhibits JHCO(3)(-) and that the biphasic dose-dependent effect of ANG-(1-7) on JHCO(3)(-) is mediated by the Mas receptors via the Na(+)/H(+) exchanger 3 (NHE3). The control value of intracellular Ca(2+) concentration ([Ca(2+)](i)), as monitored using fura-2 AM, is 101 ± 2 nM (6), and ANG-(1-7) (10(-12), 10(-9), or 10(-6)M) transiently (3 min) increases it (by 151, 102, or 52%, respectively). A779 increases the [Ca(2+)](i) (25%) but impairs the stimulatory effect of all doses of ANG-(1-7) on it. The use of BAPTA or thapsigargin suggests a correlation between the ANG-(1-7) dose-dependent effects on [Ca(2+)](i) and JHCO(3)(-). Therefore, the interaction of the opposing dose-dependent effects of ANG II and ANG-(1-7) on [Ca(2+)](i) and JHCO(3)(-) may represent an physiological regulatory mechanism of extracellular volume and/or pH changes. However, whether [Ca(2+)](i) modification is an important direct mechanism for NHE3 activation by these peptides or is a side effect of other signaling pathways will require additional studies.

Keywords: ANG-(1–7) acute direct proximal action; Na+/H+ exchanger; cytosolic calcium.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiotensin I / pharmacology*
  • Animals
  • Bicarbonates / metabolism*
  • Calcium / metabolism*
  • Dose-Response Relationship, Drug
  • Egtazic Acid / analogs & derivatives
  • Egtazic Acid / pharmacology
  • Guanidines / pharmacology
  • Kidney Tubules, Proximal / drug effects*
  • Kidney Tubules, Proximal / metabolism
  • Male
  • Methacrylates / pharmacology
  • Peptide Fragments / pharmacology*
  • Rats
  • Rats, Wistar
  • Signal Transduction / drug effects
  • Signal Transduction / physiology
  • Sodium-Hydrogen Exchangers / metabolism*
  • Thapsigargin / pharmacology


  • 3-(2-(3-guanidino-2-methyl-3-oxo-propenyl)-5-methylphenyl)-N-isopropylidene-2-methyl-acrylamide dihydrochloride
  • Bicarbonates
  • Guanidines
  • Methacrylates
  • Peptide Fragments
  • Sodium-Hydrogen Exchangers
  • Egtazic Acid
  • Thapsigargin
  • Angiotensin I
  • angiotensin I (1-7)
  • 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid
  • Calcium