8-iso-prostaglandin-F2α stimulates chloride transport in thick ascending limbs: role of cAMP and protein kinase A

Author:

Cabral Pablo D.1,Silva Guillermo B.23,Baigorria Sandra T.2,Juncos Luis A.4,Juncos Luis I.2,García Néstor H.2

Affiliation:

1. Hypertension and Vascular Research Division, Department of Internal Medicine, Henry Ford Hospital, Detroit, Michigan;

2. Department of Renal Physiology, J. Robert Cade Foundation CONICET, Cordoba;

3. Department of Renal Physiology and Hypertension, Mons. Carlos V. Cruvellier Foundation, San Juan, Argentina; and

4. Department of Physiology and Biophysics and Division of Nephrology, Department of Medicine, University of Mississippi Medical Center, Jackson, Mississippi

Abstract

Salt reabsorption by the loop of Henle controls NaCl handling and blood pressure regulation. Increased oxidative stress stimulates NaCl transport in one specific segment of the loop of Henle called the thick ascending limb (TAL). The isoprostane 8-iso-prostaglandin-F2α (8-iso-PGF2α) is one of the most abundant nonenzymatic lipid oxidation products and has been implicated in the development of hypertension. However, it is not known whether 8-iso-PGF2α regulates transport or the mechanisms involved. Because protein kinase A (PKA) stimulates NaCl transport in several nephron segments, we hypothesized that 8-iso-PGF2α increases NaCl transport in the cortical TAL (cTAL) via a PKA-dependent mechanism. We examined the effect of luminal 8-iso-PGF2α on NaCl transport by measuring chloride absorption ( JCl) in isolated microperfused cTALs. Adding 8-iso-PGF2α to the lumen increased JClby 54% (from 288.7 ± 30.6 to 446.5 ± 44.3 pmol·min−1·mm−1; P < 0.01), while adding it to the bath enhanced JClby 35% (from 236.3 ± 35.3 to 319.2 ± 39.8 pmol·min−1·mm−1; P < 0.05). This stimulation was blocked by Na-K-2Cl cotransporter inhibition. Next, we tested the role of cAMP. Basal cAMP in the cTAL was 18.6 ± 1.6 fmol·min−1·mm−1, and 8-iso-PGF2α raised it to 35.1 ± 1.4 fmol·min−1·mm−1, an increase of 94% ( P < 0.01). Because cAMP stimulates PKA, we measured JClusing the PKA-selective inhibitor H89. In the presence of H89 (10 μM), 8-iso-PGF2α failed to increase transport regardless of whether it was added to the lumen (216.1 ± 16.7 vs. 209.7 ± 23.8 pmol·min−1·mm−1; NS) or the bath (150.4 ± 32.9 vs. 127.1 ± 28.6 pmol·min−1·mm−1; NS). We concluded that 8-iso-PGF2α stimulates cAMP and increases Cl transport in cTALs via a PKA-dependent mechanism.

Publisher

American Physiological Society

Subject

Physiology

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