Angiotensin II inhibits HCO 3 − absorption via a cytochromeP-450-dependent pathway in MTAL

1999 ◽  
Vol 276 (5) ◽  
pp. F726-F736 ◽  
Author(s):  
David W. Good ◽  
Thampi George ◽  
Donna H. Wang
Keyword(s):  
Tyrosine Kinase ◽  
Kinase Inhibitors ◽  
Extracellular Fluid ◽  
Arachidonic Acid Metabolism ◽  
Sodium Balance ◽  
Thick Ascending Limb ◽  
Ang Ii ◽  
Acid Base Balance ◽  
No Donor ◽  
Cytochrome P 450

The role of ANG II in the regulation of ion reabsorption by the renal thick ascending limb is poorly understood. Here, we demonstrate that ANG II (10−8 M in the bath) inhibits [Formula: see text] absorption by 40% in the isolated, perfused medullary thick ascending limb (MTAL) of the rat. The inhibition by ANG II was abolished by pretreatment with eicosatetraynoic acid (10 μM), a general inhibitor of arachidonic acid metabolism, or 17-octadecynoic acid (10 μM), a highly selective inhibitor of cytochrome P-450 pathways. Bath addition of 20-hydroxyeicosatetraenoic acid (20-HETE; 10−8 M), the major P-450 metabolite in the MTAL, inhibited [Formula: see text] absorption, whereas pretreatment with 20-HETE prevented the inhibition by ANG II. The addition of 15-HETE (10−8 M) to the bath had no effect on [Formula: see text]absorption. The inhibition of [Formula: see text]absorption by ANG II was reduced by >50% in the presence of the tyrosine kinase inhibitors genistein (7 μM) or herbimycin A (1 μM). We found no role for cAMP, protein kinase C, or NO in the inhibition by ANG II. However, addition of the exogenous NO donor S-nitroso- N-acetylpenicillamine (SNAP; 10 μM) or the NO synthase (NOS) substratel-arginine (1 mM) to the bath stimulated [Formula: see text] absorption by 35%, suggesting that NO directly regulates MTAL[Formula: see text] absorption. Addition of 10−11 to 10−10 M ANG II to the bath did not affect [Formula: see text] absorption. We conclude that ANG II inhibits [Formula: see text]absorption in the MTAL via a cytochrome P-450-dependent signaling pathway, most likely involving the production of 20-HETE. Tyrosine kinase pathways also appear to play a role in the ANG II-induced transport inhibition. The inhibition of [Formula: see text]absorption by ANG II in the MTAL may play a key role in the ability of the kidney to regulate sodium balance and extracellular fluid volume independently of acid-base balance.

ANG II controls Na+-K+( NH 4 + )-2Cl−cotransport via 20-HETE and PKC in medullary thick ascending limb

1998 ◽  
Vol 274 (4) ◽  
pp. C1047-C1056 ◽  
Author(s):  
Hassane Amlal ◽  
Christian LeGoff ◽  
Catherine Vernimmen ◽  
Manoocher Soleimani ◽  
Michel Paillard ◽  
...  
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
Phospholipase C ◽  
Thick Ascending Limb ◽  
Ang Ii ◽  
Diacylglycerol Lipase ◽  
Medullary Thick Ascending Limb ◽  
Kinase C ◽  
Cell Ph ◽  
Cytochrome P 450

Cell pH was monitored in medullary thick ascending limbs to determine effects of ANG II on Na+-K+([Formula: see text])-2Cl−cotransport. ANG II at 10−16to 10−12 M inhibited 30–50% ( P < 0.005), but higher ANG II concentrations were stimulatory compared with the 10−12 M ANG II level cotransport activity; eventually, 10−6 M ANG II stimulated 34% cotransport activity ( P < 0.003). Inhibition by 10−12M ANG II was abolished by phospholipase C (PLC), diacylglycerol lipase, or cytochrome P-450-dependent monooxygenase blockade; 10−12 M ANG II had no effect additive to inhibition by 20-hydroxyeicosatetranoic acid (20-HETE). Stimulation by 10−6 M ANG II was abolished by PLC and protein kinase C (PKC) blockade and was partially suppressed when the rise in cytosolic Ca2+ was prevented. All ANG II effects were abolished by DUP-753 (losartan) but not by PD-123319. Thus ≤10−12 M ANG II inhibits via 20-HETE, whereas ≥5 × 10−11 M ANG II stimulates via PKC Na+-K+([Formula: see text])-2Cl−cotransport; all ANG II effects involve AT1 receptors and PLC activation.

Renal cytochrome P-450-arachidonic acid metabolism: localization and hormonal regulation in SHR

1992 ◽  
Vol 262 (4) ◽  
pp. F591-F599 ◽  
Author(s):  
K. Omata ◽  
N. G. Abraham ◽  
M. L. Schwartzman
Keyword(s):  
Hormonal Regulation ◽  
Distribution Patterns ◽  
Arachidonic Acid Metabolism ◽  
Proximal Tubules ◽  
Ang Ii ◽  
Spontaneously Hypertensive ◽  
Nephron Segments ◽  
Wistar Kyoto ◽  
Cytochrome P 450 ◽  
Stimulation Of

Epoxygenase and omega- and omega-1-hydroxylases are the major cytochrome P-450-arachidonate (P-450-AA) metabolizing enzymes in renal tissues. We measured P-450-AA metabolism in single nephron segments and determined the tubular localization of this activity in spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY). Formation of 20-hydroxyeicosatetraenoic acid (20-HETE), the product of AA omega-hydroxylase was specifically localized in the entire proximal tubules (S1, S2, and S3 segments), whereas formation of 19-HETE, the product of omega-1-hydroxylase and epoxyeicosatrienoic acids (EETs), products of AA epoxygenase, was demonstrable throughout the tubule. Although distribution patterns were similar in SHR and WKY, formation of 19- and 20-HETE in the proximal tubules was higher in SHR, whereas the formation of EETs was not different between the two strains. In the proximal tubules, angiotensin II (ANG II) significantly stimulated epoxygenase activity (EETs formation), whereas parathyroid hormone (PTH) and epidermal growth factor (EGF) had no effect on epoxygenase but significantly stimulated omega-hydroxylase activity (20-HETE formation). Because P-450-AA metabolites have a wide and contrasting spectrum of biological and renal effects, from vasodilation to vasoconstriction and from inhibition to stimulation of Na(+)-K(+)-adenosinetriphosphatase, their localization to the specific nephron segments and differential stimulation of their formation by ANG II, PTH, and EGF may contribute not only to renal hemodynamics and blood pressure regulation but also to the regulation of renal sodium and water balance.

scholarly journals Nitric oxide inhibits sodium/hydrogen exchange activity in the thick ascending limb

1999 ◽  
Vol 277 (3) ◽  
pp. F377-F382 ◽  
Author(s):  
Jeffrey L. Garvin ◽  
Nancy J. Hong
Keyword(s):  
Nitric Oxide ◽  
Steady State ◽  
Hydrogen Exchange ◽  
Thick Ascending Limb ◽  
Acid Base Balance ◽  
No Donor ◽  
Base Balance ◽  
Dimethyl Amiloride ◽  
Oxide Synthase ◽  
Spermine Nonoate

Nitric oxide (NO) inhibits transport in various nephron segments, and the thick ascending limb (TAL) expresses nitric oxide synthase (NOS). However, the effects of NO on TAL transport have not been extensively studied. We tested the hypothesis that NO inhibits apical and basolateral Na+/H+exchange by the TAL by measuring intracellular pH (pHi) of isolated, perfused rat TALs using the fluorescent dye 2′,7′-bis-(2-carboxyethyl)-5-(and-6)-carboxyfluorescein (BCECF). The NO donor spermine NONOate (SPM, 10 μM) decreased steady-state pHi in medullary TALs from 7.18 ± 0.13 to 7.13 ± 0.14 ( P < 0.02), whereas controls did not decrease significantly. We next measured the buffering capacity of medullary TALs and the rate at which they recovered from acid loads to investigate the mechanism whereby NO reduces steady-state pHi. SPM decreased H+ flux ( J H) from 2.41 ± 0.66 to 0.97 ± 0.19 pmol ⋅ min−1 ⋅ mm−1, 55%. To assure that the decrease in J H was due to NO, another donor, nitroglycerin (NTG; 10 μM), was used. NTG decreased J H from 1.65 ± 0.11 to 1.07 ± 0.24 pmol ⋅ min−1 ⋅ mm−1, 37%. To determine the relative contributions of the apical and basolateral Na+/H+exchangers, 5-( N, N-dimethyl)amiloride (DMA; 100 μM) was added to either bath or lumen. With DMA added to the bath, SPM decreased J H from 4.78 ± 1.08 to 2.74 ± 0.54 pmol ⋅ min−1 ⋅ mm−1, an inhibition of 41%; and with DMA added to the lumen, SPM decreased J H from 2.31 ± 0.29 to 1.74 ± 0.27 pmol ⋅ min−1 ⋅ mm−1, a reduction of 26%. Addition of DMA alone to both bath and lumen resulted in an 87% inhibition of J H. We conclude that NO inhibits both apical and basolateral Na+/H+exchangers and consequently may play an important role in regulating pHi and may alter acid/base balance by directly affecting bicarbonate absorption in the TAL.

scholarly journals Tyrosine Kinase and Mitogen-Activated Protein Kinase/Extracellularly Regulated Kinase Differentially Regulate Intracellular Calcium Concentration Responses to Angiotensin II/III and Bradykinin in Rat Cortical Thick Ascending Limb

Endocrinology ◽  
2006 ◽  
Vol 147 (1) ◽  
pp. 451-463 ◽  
Author(s):  
Annette Hus-Citharel ◽  
Xavier Iturrioz ◽  
Pierre Corvol ◽  
Jeannine Marchetti ◽  
Catherine Llorens-Cortes
Keyword(s):  
Protein Kinase ◽  
Tyrosine Kinase ◽  
Intracellular Calcium ◽  
Calcium Concentration ◽  
Receptor Type ◽  
Intracellular Calcium Concentration ◽  
Thick Ascending Limb ◽  
Ang Ii ◽  
Na Transport ◽  
Herbimycin A

The cortical thick ascending limb (CTAL) coexpresses angiotensin (Ang) II/Ang III receptor type 1A (AT1A-R) and bradykinin (BK) receptor type 2 (B2-R). In several cell types, these two receptors share the same signaling pathways, although their physiological functions are often opposite. In CTAL, little is known about the intracellular transduction events leading to the final physiological response induced by these two peptides. We investigated and compared in this segment the action of Ang II/III and BK on intracellular calcium concentration ([Ca2+]i) response and metabolic CO2 production, an index of Na+ transport, by using inhibitors of protein kinase C (bisindolylmaleimide), Src tyrosine kinase (herbimycin A and PP2), and MAPK/ERK (PD98059 and UO126). Ang II/III and BK (10−7 mol/liter) released Ca2+ from the same intracellular pools but activated different Ca2+ entry pathways. Ang II/III- or BK-induced [Ca2+]i increases were similarly potentiated by bisindolylmaleimide. Herbimycin A and PP2 decreased similarly the [Ca2+]i responses induced by Ang II/III and BK. In contrast, PD98059 and UO126 affected the effects of BK to a larger extent than those of Ang II/III. Especially, the Ca2+ influx induced by BK was more strongly inhibited than that induced by Ang II/III in the presence of both compounds. The Na+ transport was inhibited by BK and stimulated by Ang II/III. The inhibitory action of BK on Na+ transport was blocked by UO126, whereas the stimulatory response of Ang II/III was potentiated by UO126 but blocked by bisindolylmaleimide. These data suggest that the inhibitory effect of BK on Na+ transport seems to be directly mediated by an increase in Ca2+ influx dependent on MAPK/ERK pathway activation. In contrast, the stimulatory effect of Ang II/III on Na+ transport is more complex and involves PKC and MAPK/ERK pathways.

Aldosterone inhibits HCO-3 absorption via a nongenomic pathway in medullary thick ascending limb

2002 ◽  
Vol 283 (4) ◽  
pp. F699-F706 ◽  
Author(s):  
David W. Good ◽  
Thampi George ◽  
Bruns A. Watts
Keyword(s):  
Actinomycin D ◽  
Renal Tubule ◽  
Extracellular Fluid ◽  
Transepithelial Transport ◽  
Thick Ascending Limb ◽  
The Novel ◽  
Acid Base Balance ◽  
Acid Base ◽  
Medullary Thick Ascending Limb ◽  
Base Balance

Rapid actions of aldosterone that are independent of transcription and translation have been described in a variety of cells; however, whether nongenomic pathways mediate aldosterone-induced regulation of renal tubule transport has not been determined. We report here that aldosterone induces rapid (<3.5 min) inhibition of HCO[Formula: see text] absorption in the medullary thick ascending limb (MTAL) of the rat. This inhibition is observed over the physiological range of hormone concentrations (IC50 ≃ 0.6 nM) and is not affected by pretreatment with actinomycin D (12.5 μg/ml), cycloheximide (40 μg/ml), or spironolactone (10 μM). The glucocorticoids dexamethasone, cortisol, and corticosterone (1 or 500 nM) did not affect HCO[Formula: see text]absorption in the absence or presence of carbenoxolone. Thus the specificity of rapid aldosterone action is not dependent on 11β-hydroxysteroid dehydrogenase activity. The inhibition by aldosterone is additive to inhibition by angiotensin II and vasopressin, indicating that these factors regulate MTAL transport through distinct pathways. These results demonstrate that aldosterone inhibits HCO[Formula: see text] absorption in the MTAL via a pathway that is rapid, highly selective, independent of transcription and protein synthesis, and not mediated through the classic mineralocorticoid receptor. The results establish a role for nongenomic pathways in mediating aldosterone-induced regulation of transepithelial transport in the mammalian kidney. The novel action of aldosterone to inhibit luminal acidification in the MTAL may play a role in enabling the kidney to regulate acid-base balance independently of Na+ balance and extracellular fluid volume.

Angiotensin II phosphorylation of extracellular signal-regulated kinases in rat anterior pituitary cells

2003 ◽  
Vol 285 (3) ◽  
pp. E645-E653 ◽  
Author(s):  
Cecilia Suárez ◽  
Graciela Díaz-Torga ◽  
Arturo Gonzalez-Iglesias ◽  
Jorge Vela ◽  
Alejandro Mladovan ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Intracellular Calcium ◽  
Kinase Inhibitors ◽  
Maximum Effect ◽  
Calcium Stores ◽  
Pituitary Cells ◽  
Ang Ii ◽  
Src Tyrosine Kinase ◽  
Extracellular Signal ◽  
Rat Pituitary

We studied the effects of ANG II on extracellular signal-regulated kinase (ERK)1/2 phosphorylation in rat pituitary cells. ANG II increased ERK phosphorylation in a time- and concentration-dependent way. Maximum effect was obtained at 5 min at a concentration of 10-100 nM. The effect of 100 nM ANG II was blocked by the AT1 antagonist DUP-753, by the phospholipase C (PLC) inhibitor U-73122, and by the MAPK kinase (MEK) antagonist PD-98059. The ANG II-induced increase in phosphorylated (p)ERK was insensitive to pertussis toxin blockade and PKC depletion or inhibition. The effect was also abrogated by chelating intracellular calcium with BAPTA-AM or TMB-8 by depleting intracellular calcium stores with a 30-min pretreatment with EGTA and by pretreatment with herbimycin A and PP1, two c-Src tyrosine kinase inhibitors. It was attenuated by AG-1478, an inhibitor of epidermal growth factor receptor (EGFR) activation. Therefore, in the rat pituitary, the increase of pERK is a Gq- and PLC-dependent process, which involves an increase in intracellular calcium and activation of a c-Src tyrosine kinase, transactivation of the EGFR, and the activation of MEK. Finally, the response of ERK activation by ANG II is altered in hyperplastic pituitary cells, in which calcium mobilization evoked by ANG II is also modified.

scholarly journals Effect of catecholamines on rat medullary thick ascending limb chloride transport: interaction with angiotensin II

2010 ◽  
Vol 298 (4) ◽  
pp. R954-R958 ◽  
Author(s):  
Michel Baum
Keyword(s):  
Chloride Transport ◽  
Extracellular Fluid ◽  
Distal Tubule ◽  
Transport Rate ◽  
Thick Ascending Limb ◽  
Ang Ii ◽  
Adrenergic Agonists ◽  
Nephron Segments ◽  
Medullary Thick Ascending Limb ◽  
Stimulation Of

Previous studies have shown that in proximal and distal tubule nephron segments, peritubular ANG II stimulates sodium chloride transport. However, ANG II inhibits chloride transport in the medullary thick ascending limb (mTAL). Because ANG II and catecholamines are both stimulated by a decrease in extracellular fluid volume, the purpose of this study was to examine whether there was an interaction between ANG II and catecholamines to mitigate the inhibition in chloride transport by ANG II. In isolated perfused rat mTAL, 10−8 M bath ANG II inhibited transport (from a basal transport rate of 165.6 ± 58.8 to 58.8 ± 29.4 pmol·mm−1·min−1; P < 0.01). Bath norepinephrine stimulated chloride transport (from a basal transport rate of 298.1 ± 31.7 to 425.2 ± 45.8 pmol·mm−1·min−1; P < 0.05) and completely prevented the inhibition in chloride transport by ANG II. The stimulation of chloride transport by norepinephrine was mediated entirely by its β-adrenergic effect; however, both the β- and α-adrenergic agonists isoproterenol and phenylephrine prevent the ANG II-mediated inhibition in chloride transport. In the presence of 10−5 M propranolol, the effect of norepinephrine to prevent the inhibition of chloride transport by ANG II was still present. These data are consistent with an interaction of both α- and β-catecholamines and ANG II on net chloride transport in the mTAL.

Sign in / Sign up

Export Citation Format

Share Document