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1 Department of Physiology and Biophysics, University of Southern California Keck School of Medicine, Los Angeles, California, USA
2 Core Proteomics Laboratory, Kidney Disease Program, Department of Medicine, University of Louisville, Louisville, Kentucky, USA
3 Department of Physiology and Biophysics, University of South Florida, Tampa, Florida, USA
* To whom correspondence should be addressed. E-mail: mcdonoug{at}usc.edu.
Angiotensin-converting enzyme (ACE) inhibitors such as captopril, which block angiotensin II (ANG II) formation, are commonly used for treatment of hypertension. There is substantial evidence that the proximal tubule (PT) is a primary target site for captopril but the molecular mechanisms for its action in PT are not well defined. The aim of this study was to determine the physiologic and molecular changes in PT provoked by acute captopril treatment in the absence of changes in blood pressure or GFR. Captopril (infused at 12 µg/min for 20 min) did not change blood pressure or GFR but induced an immediate (<10 min) increase in PT flow measured with a non-obstructive optical method (to 117 ± 14% of baseline) along with a rapid diuresis from 2.1 ± 0.6 mg/min (baseline) to 3.7 ± 0.9 mg/min (captopril). Captopril also provoked a significant retraction of PT NHE3, NHERF-1, myosin-VI, and NaPi2, but not ACE, out of apical microvillus-enriched membranes. Proteomic analysis with MALDI-TOF MS revealed an additional eight abundant membrane-associated proteins that redistributed out of the microvillus-enriched membrane during captopril treatment: megalin, myosin II-A, clathrin, aminopeptidase N, DPPIV, ezrin, moesin, and vacuolar H+-ATPase subunit 
2. In summary, captopril can rapidly depress PT reabsorption in the absence of a change in GFR or BP and provokes the redistribution of a set of transporters and transporter-associated proteins that likely participate in the decrease in PT reabsorption and may also contribute to the blood pressure lowering effect of ACE inhibitors.
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