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Reducing blood pressure in SHR with enalapril provokes redistribution of NHE3, NaPi2, and NCC and decreases NaPi2 and ACE abundance

Department of Physiology and Biophysics, University of Southern California Keck School of Medicine, Los Angeles, California

Submitted 22 January 2007 ; accepted in final form 18 July 2007

To determine the effects of long-term angiotensin-converting enzyme inhibition (ACEI) and blood pressure (BP) lowering on renal sodium transporter abundance and distribution in spontaneously hypertensive rats (SHR), 9-wk SHR were treated with enalapril (30 mg·kg^–1·day^–1) for 4 wk. BP decreased from 156 ± 4 to 96 ± 8 mmHg. Na⁺/H⁺ exchanger isoform 3 (NHE3) and Na⁺-P_i cotransporter type 2 (NaPi2) localized to the body of the microvilli (MV) in normotensive rat strains. In untreated SHR, NHE3 partially retracted from the body to base of the MV and NaPi2 retracted to subapical vesicles. After enalapril treatment of SHR, NHE3 fully retracted to the base of the MV and, by density gradient fractionation, NHE3, NaPi2, dipeptidyl peptidase IV, myosin VI, Na-Cl cotransporter, and cortical Na-K-Cl cotransporter redistributed from low-density (apical enriched) to high-density (endosome enriched) membranes. Enalapril decreased total abundance of myosin VI (to 0.51 ± 0.18 of untreated), ACE (0.67 ± 0.22), and cortical NaPi2 (0.83 ± 0.10). Normalizing SHR BP with HRH (7.5 mg/day hydralazine, 0.15 mg/day reserpine, and 3 mg/day hydrochlorothiazide) did not change Na⁺ transporter density distribution or abundance. We conclude that lowering BP to normal levels in SHR does not normalize Na⁺ transporter distribution, rather, chronic ACEI treatment provokes retraction of Na⁺ transporters and associated proteins from transport-relevant domains of apical membranes and/or reduces their abundance.

hypertension; kidney; Na transporter; ACE inhibitor; triple therapy

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