Effects of ACE inhibition on proximal tubule sodium transport.
Angiotensin-converting enzyme (ACE) inhibitors such as captopril, which block 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 physiological and molecular changes in PT provoked by acute captopril treatment in the absence of changes in blood pressure or glomerular filtration rate (GFR). Captopril (infused at 12 microg/min for 20 min) did not change blood pressure or GFR but induced an immediate (<10 min) increase in PT flow measured with a nonobstructive 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 Na(+)/H(+) exchanger isoform 3 (NHE3), NHE regulatory factor (NHERF)-1, myosin-VI, and Na(+)-P(i) cotransporter type 2 (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 beta(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.
Leong
Patrick K K
PK
Department of Physiology and Biophysics, University of Southern California Keck School of Medicine, Los Angeles 90089-9142, USA.
Devillez
Angela
A
Sandberg
Monica B
MB
Yang
Li E
LE
Yip
Daniel K P
DK
Klein
Jon B
JB
McDonough
Alicia A
AA
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D001794:Blood Pressure; D002216:Captopril / Q000494:pharmacology*; D005919:Glomerular Filtration Rate; D007687:Kidney Tubules, Proximal / Q000502:physiology*; D008297:Male; D013058:Mass Spectrometry; D008565:Membrane Proteins / Q000187:drug effects / Q000502:physiology; D040901:Proteomics; D051381:Rats; D017207:Rats, Sprague-Dawley; D012964:Sodium / Q000493:pharmacokinetics*; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
D000806:Angiotensin-Converting Enzyme Inhibitors; D008565:Membrane Proteins; D002216:Captopril; D012964:Sodium