Luminal angiotensin II stimulates rat medullary thick ascending limb chloride transport in the presence of basolateral norepinephrine

Abstract

Baum M. Luminal angiotensin II stimulates rat medullary thick ascending limb chloride transport in the in the presence of basolateral norepinephrine. Am J Physiol Renal Physiol 310: F294 -F299, 2016. First published December 9, 2015 doi:10.1152/ajprenal.00447.2015.-Angiotensin II (ANG II) is secreted by the proximal tubule resulting in a luminal concentration that is 100-to 1,000-fold greater than that in the blood. Luminal ANG II has been shown to stimulate sodium transport in the proximal tubule and distal nephron. Surprisingly, luminal ANG II inhibits NaCl transport in the medullary thick ascending limb (mTAL), a nephron segment responsible for a significant amount of NaCl absorption from the glomerular ultrafiltrate. We confirmed that addition of 10 Ϫ8 M ANG II to the lumen inhibited mTAL chloride transport (220 Ϯ 19 to 165 Ϯ 25 pmol·mm, P Ͻ 0.01) and examined whether an interaction with basolateral norepinephrine existed to simulate the in vivo condition of an innervated tubule. We found that in the presence of a 10 Ϫ6 M norepinephrine bath, luminal ANG II stimulated mTAL chloride transport from 298 Ϯ 18 to 364 Ϯ 42 pmol·mm NKCC2; chloride transport; norepinephrine; hormonal interaction; microperfusion ANGIOTENSIN II (ANG II) LEVELS INCREASE with volume depletion, which results in an increase in renal sodium absorption that helps to maintain a constant extracellular fluid volume. In addition to the systemic renin-angiotensin system, the proximal tubule has all of the metabolic machinery to generate the peptide hormone ANG II and secrete it into the tubular lumen (8,19,22,23,25). The concentration of ANG II in the blood is approximately 10 -100 pM (8, 25), whereas studies that have directly measured ANG II from the proximal tubule lumen using in vivo micropuncture demonstrate that the concentration of ANG II is 100-to 1,000-fold higher in the tubular lumen than in the blood (8,25,34). In vivo microperfusion studies in which the glomerular ultrafiltrate is blocked and an artificial ultrafiltrate is used to directly perfuse the proximal tubule have shown that the proximal tubule generates and secretes ANG II into the tubular lumen (8). The effect of luminal ANG II may thus play a significant role in the regulation of tubular transport. ANG II has been shown to stimulate transport of sodium in the proximal tubule when added to the bathing solution of proximal tubules perfused in vitro (33). Addition of ANG II had no effect on transport when added to the luminal perfusate of proximal tubules perfused in vitro, but it stimulated proximal tubule sodium transport when the endogenous production of ANG II was inhibited by enalaprilat, which is consistent with endogenous luminal secretion affecting proximal tubule transport of sodium (6). In vitro microperfusion studies of the distal convoluted tubule have also found that ANG II had a direct effect on the apical membrane by stimulating sodium transport (39). ANG II also increases sodium transport in the cortical collecting tubule, which is dependent on pendrin, an ap...

Thick Ascending Limb Sodium Transport in the Pathogenesis of Hypertension

“…At physiological concentrations, ANG II inhibits Cl Ϫ reabsorption by thick ascending limbs (34,35,379). These results are at odds with the generally held view that this hormone stimulates salt retention by the kidney.…”

“…However, in vivo, ANG II may in fact stimulate salt reabsorption by this segment. Alone, 10 Ϫ9 M ANG II inhibits Cl Ϫ reabsorption, but this same concentration stimulates transport if tubules have been pretreated with either NE (34,35) or cAMP (35). Similarly, ANG II was found to elevate oxygen consumption, a measure of active transport, in a sustained manner after a transient inhibition in thick ascending limb suspensions treated with vasopressin, which enhances intracellular cAMP (632).…”

“…AT 2 receptors have been reported to either have no effect (379) or mediate inhibition of NKCC2 activity (292). Inhibition of transport was reported to 1) be mediated by 20-HETE and not cAMP (14); 2) involve cAMP because a protein kinase A inhibitor could prevent the reduction (35); 3) be due to a decrease in cAMP (632); and 4) be mediated by NO (292). In contrast, the stimulation has been reported to 1) be mediated by protein kinase C (14); 2) somehow involve cAMP and protein kinase A (35); and 3) be mediated by elevated O 2…”

Angiotensin II-mediated hypertension impairs nitric oxide-induced NKCC2 inhibition in thick ascending limbs

“…Thus, differences in NKCC2 activity caused by changes in NO production or effect would not be present. Finally, other signals that are not present in isolated and perfused THALs might be necessary to observe increases in basal NKCC2 activity (3). Regardless of whether basal NKCC2 activity is different in isolated and perfused THALs from vehicle-vs. ANG II-hypertensive rats, our data conclusively demonstrate that NO-mediated inhibition of NKCC2 activity is impaired in this model of hypertension.…”

Mechanistic interactions of uromodulin with the thick ascending limb: perspectives in physiology and hypertension

“…AngII inhibits Clreabsorption in isolated rat TAL tubules in vitro in microperfusion flux studies, but stimulates transport if treated with noradrenaline or cAMP [155,156]. NKCC2 has been shown to be inhibited by 20-HETE and NO via AngII signalling [157].…”