title: 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.
abstract: BACKGROUND
  Collectrin, a homologue of angiotensin converting enzyme 2, is expressed in pancreatic beta cells and renal proximal tubular and collecting duct cells under the control of hepatocyte nuclear factors-1alpha and -1beta. 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.
  
  
  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, alpha-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, alpha-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 micromol/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.
authors.affiliation: Department of Medicine and Clinical Science, Okayama University Graduate School of Medicine, 2-5-1 Shikata-cho, Okayama 700-8558, Japan.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Yasuhara
authors.forename: Jun
authors.initials: J
authors.lastname: Wada
authors.forename: Sandra M
authors.initials: SM
authors.lastname: Malakauskas
authors.forename: Yanling
authors.initials: Y
authors.lastname: Zhang
authors.forename: Jun
authors.initials: J
authors.lastname: Eguchi
authors.forename: Atsuko
authors.initials: A
authors.lastname: Nakatsuka
authors.forename: Kazutoshi
authors.initials: K
authors.lastname: Murakami
authors.forename: Motoko
authors.initials: M
authors.lastname: Kanzaki
authors.forename: Sanae
authors.initials: S
authors.lastname: Teshigawara
authors.forename: Kazuya
authors.initials: K
authors.lastname: Yamagata
authors.forename: Thu H
authors.initials: TH
authors.lastname: Le
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Makino
mesh_terms: D000450:Aldosterone / Q000652:urine; D000818:Animals; D051399:Aquaporin 2 / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects; D002460:Cell Line; D037222:Collectins / Q000096:biosynthesis*; D053503:Epithelial Sodium Channels; D051538:Hepatocyte Nuclear Factor 1-alpha / Q000378:metabolism; D051539:Hepatocyte Nuclear Factor 1-beta / Q000378:metabolism; D006973:Hypertension / Q000139:chemically induced* / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000378:metabolism; D007685:Kidney Tubules, Collecting / Q000378:metabolism; D007687:Kidney Tubules, Proximal / Q000378:metabolism; D046912:Multiprotein Complexes / Q000378:metabolism*; D006180:Proton-Translocating ATPases / Q000378:metabolism; D050765:Qa-SNARE Proteins / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D050600:SNARE Proteins / Q000378:metabolism*; D012965:Sodium Chloride / Q000633:toxicity*; D015854:Up-Regulation / Q000187:drug effects*; D050988:Vesicle-Associated Membrane Protein 2 / Q000378:metabolism
chemical_list: C496025:Aqp2 protein, rat; D051399:Aquaporin 2; D037222:Collectins; D053503:Epithelial Sodium Channels; D051538:Hepatocyte Nuclear Factor 1-alpha; D046912:Multiprotein Complexes; D050765:Qa-SNARE Proteins; D034741:RNA, Small Interfering; D050600:SNARE Proteins; D050988:Vesicle-Associated Membrane Protein 2; D051539:Hepatocyte Nuclear Factor 1-beta; D012965:Sodium Chloride; D000450:Aldosterone; D006180:Proton-Translocating ATPases