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(Circulation. 2008;118:2146-2155.)
© 2008 American Heart Association, Inc.

Hypertension

Collectrin Is Involved in the Development of Salt-Sensitive Hypertension by Facilitating the Membrane Trafficking of Apical Membrane Proteins via Interaction With Soluble N-Ethylmaleiamide-Sensitive Factor Attachment Protein Receptor Complex

Akihiro Yasuhara, MD; Jun Wada, MD, PhD; Sandra M. Malakauskas, PhD; Yanling Zhang, MD, PhD; Jun Eguchi, MD, PhD; Atsuko Nakatsuka, MD; Kazutoshi Murakami, MD; Motoko Kanzaki, MD; Sanae Teshigawara, MD; Kazuya Yamagata, MD, PhD; Thu H. Le, MD, PhD; Hirofumi Makino, MD, PhD

From the Department of Medicine and Clinical Science, Okayama University Graduate School of Medicine, Okayama, Japan (A.Y., J.W., J.E., A.N., K.M., M.K., S.T., H.M.); University of Alabama, Birmingham (S.M.M.); Department of Nephrology, Third Hospital Hebei Medical University, Shijiazhuang, PR China (Y.Z.); Department of Medical Biochemistry, Faculty of Medical Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan (K.Y.); and Department of Medicine and Pathology, Duke University and Durham Veterans Affairs Medical Center, Durham, NC (T.H.L.).

Correspondence to Jun Wada, MD, PhD, Department of Medicine and Clinical Science, Okayama University Graduate School of Medicine, 2–5–1, Shikata-cho, Okayama 700–8558, Japan. E-mail junwada{at}md.okayama-u.ac.jp

Received April 19, 2008; accepted September 17, 2008.

Background— Collectrin, a homologue of angiotensin converting enzyme 2, is expressed in pancreatic β cells and renal proximal tubular and collecting duct cells under the control of hepatocyte nuclear factors-1 and -1β. Because collectrin interacts with the soluble N-ethylmaleiamide-sensitive factor attachment protein receptor (SNARE) complexes, we investigated whether collectrin is involved in sodium handling in hypertension by vesicle trafficking of apical membrane proteins.

Methods and Results— Collectrin physically interacts with the SNARE complex: snapin, synaptosomal-associated protein 23 kDa, syntaxin-4, and vesicle-associated membrane protein-2 in mIMCD-3 cells. siRNA knockdown of collectrin resulted in a reduction in membrane-associated aquaporin-2, -epithelial Na⁺ channel, and H⁺-ATPase. Collectrin and SNARE proteins were abundantly expressed in collecting ducts of Wistar-Kyoto rats. Wistar-Kyoto rats and spontaneously hypertensive rats 7 weeks of age were subjected to normal-salt (1% NaCl) and high-salt (8% NaCl) chow for 10 weeks. High-salt chow prominently elevated blood pressure, oral intake, and urinary excretion of NaCl and water in both groups. Although urinary excretion of aldosterone was significantly suppressed in both groups, collectrin expression was upregulated and associated with the maintenance of aquaporin-2, -epithelial Na⁺ channel, and H⁺-ATPase in membrane fractions. Collectrin promoter activities and mRNA and protein expressions were upregulated and ubiquitinated collectrin was reduced by high NaCl (175 to 225 mmol/L) and not altered by 1 µmol/L aldosterone in mIMCD-3 cells.

Conclusions— Upregulation of collectrin by high NaCl independent of aldosterone functionally links to the trafficking of apical membrane proteins via the SNARE complex, and collectrin may be responsible for the sodium retention in salt-sensitive hypertension.

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CLINICAL PERSPECTIVE

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