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. 2013 Aug 15;305(4):F568-73.
doi: 10.1152/ajprenal.00613.2012. Epub 2013 May 22.

Endothelin-1 inhibits sodium reabsorption by ET(A) and ET(B) receptors in the mouse cortical collecting duct

Affiliations

Endothelin-1 inhibits sodium reabsorption by ET(A) and ET(B) receptors in the mouse cortical collecting duct

I Jeanette Lynch et al. Am J Physiol Renal Physiol. .

Abstract

The collecting duct (CD) is a major renal site for the hormonal regulation of Na homeostasis and is critical for systemic arterial blood pressure control. Our previous studies demonstrated that the endothelin-1 gene (edn1) is an early response gene to the action of aldosterone. Because aldosterone and endothelin-1 (ET-1) have opposing actions on Na reabsorption (JNa) in the kidney, we postulated that stimulation of ET-1 by aldosterone acts as a negative feedback mechanism, acting locally within the CD. Aldosterone is known to increase JNa in the CD, in part, by stimulating the epithelial Na channel (ENaC). In contrast, ET-1 increases Na and water excretion through its binding to receptors in the CD. To date, direct measurement of the quantitative effect of ET-1 on transepithelial JNa in the isolated in vitro microperfused mouse CD has not been determined. We observed that the CD exhibits substantial JNa in male and female mice that is regulated, in part, by a benzamil-sensitive pathway, presumably ENaC. ENaC-mediated JNa is greater in the cortical CD (CCD) than in the outer medullary CD (OMCD); however, benzamil-insensitive JNa is present in the CCD and not in the OMCD. In the presence of ET-1, ENaC-mediated JNa is significantly inhibited. Blockade of either ETA or ETB receptor restored JNa to control rates; however, only ETA receptor blockade restored a benzamil-sensitive component of JNa. We conclude 1) Na reabsorption is mediated by ENaC in the CCD and OMCD and also by an ENaC-independent mechanism in the CCD; and 2) ET-1 inhibits JNa in the CCD through both ETA and ETB receptor-mediated pathways.

Keywords: aldosterone; collecting duct; endothelin-1; kidney; mineralocorticoid; sodium reabsorption.

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Figures

Fig. 1.
Fig. 1.
Effect of time on Na reabsorption, JNa, in the cortical collecting duct (CCD) of male and female mice. JNa during period 1 is not different from period 2 in male (A) or female (B) mice (male control 72.1 ± 17.9 vs. control 76.8 ± 15.7, P = NS, n = 4; female control 61.4 ± 9.1 vs. control 72.1 ± 6.4, P = NS, n = 3). Extended line connects the means ± SE for the 2 experimental periods.
Fig. 2.
Fig. 2.
Effect of luminal benzamil (1 μm) on Na reabsorption, JNa, in the CCD of male (A) and female (B) mice. Benzamil significantly inhibited JNa in male and female mice (male control 72.6 ± 8.6 vs. benzamil 43.8 ± 8.7, *P < 0.05, n = 6; female control 67.8 ± 17.9 vs. benzamil 41.1 ± 18.0, *P < 0.05, n = 6). Extended line connects the means ± SE for the 2 experimental periods.
Fig. 3.
Fig. 3.
Effect of luminal hydrochlorothiazide (HCTZ; 100 μM) on benzamil-insensitive Na reabsorption, JNa, in the CCD of male mice. HCTZ did not significantly inhibit JNa in male mice (control 42.3 ± 4.8 vs. HCTZ 50.3 ± 4.8, P = NS, n = 4). Extended line connects the means ± SE for the 2 experimental periods.
Fig. 4.
Fig. 4.
Effect of luminal benzamil (1 μM) on Na reabsorption, JNa, in the OMCD of male mice. Benzamil significantly inhibited JNa in the OMCD of male mice (control 33.1 ± 5.5 vs. benzamil 4.8 ± 5.3; *P < 0.05, n = 4). Extended line connects the means ± SE for the 2 experimental periods.
Fig. 5.
Fig. 5.
Effect of benzamil in the presence of endothelin-1 (ET-1) on Na reabsorption, JNa, in the CCD of male mice. In the presence of ET-1, benzamil did not significantly inhibit Na reabsorption (ET-1 26.8 ± 7.2 vs. ET-1 + benzamil 12.5 ± 3.2, P = 0.12, n = 6). Extended line connects the means ± SE for the 2 experimental periods.
Fig. 6.
Fig. 6.
Effect of ET-1 on benzamil-insensitive Na reabsorption, JNa, in the CCD of male mice. In the presence of benzamil, ET-1 did not significantly inhibit Na reabsorption (benzamil 40.7 ± 6.6 vs. benzamil + ET-1 49.3 ± 8.2, P = NS, n = 3). Extended line connects the means ± SE for the 2 experimental periods.
Fig. 7.
Fig. 7.
Effect of benzamil in the presence of ET-1 and the ETA receptor inhibitor BQ-123 (A) or ETB receptor inhibitor BQ-788 (B) on Na reabsorption in the CCD of male mice. Benzamil significantly inhibited JNa in the presence of ET-1 plus ETA receptor inhibitor BQ-123 (ET-1 + BQ123 control 79.8 ± 8.9 vs. benzamil 52.8 ± 8.3, *P < 0.05, n = 6) but did not inhibit JNa in the presence of ET-1 plus ETB receptor inhibitor BQ-788 (ET-1 + BQ-788 control 79.2 ± 19.4 vs. benzamil 75.9 ± 13.4, P = NS). Extended line connects the means ± SE for the 2 experimental periods.
Fig. 8.
Fig. 8.
ET-1 receptor inhibitors block ET-1 regulation of Na reabsorption, JNa. ET-1 significantly inhibited JNa (basal control 72.6 ± 8.6 vs. ET-1 control 26.8 ± 7.2, P < 0.05, n = 6). Benzamil significantly inhibited JNa in the absence of ET-1 (basal control 72.6 ± 8.6 vs. benzamil 43.8 ± 8.7, P < 0.05, n = 6) and in the presence of ET-1 plus the ETA receptor inhibitor BQ-123 (ET-1 + BQ-123 control 79.8 ± 8.9 vs. benzamil 52.8 ± 8.3, P < 0.05, n = 6). Benzamil did not inhibit JNa in the presence of ET-1 plus the ETB receptor inhibitor BQ-788 (ET-1 + BQ-788 control 79.2 ± 19.4 vs. benzamil 75.9 ± 13.4, P = NS). *P < 0.05, compared with control of the same condition. **P < 0.05, compared with basal control.

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