title: Hyperuricemia induces hypertension through activation of renal epithelial sodium channel (ENaC).
abstract: OBJECTIVE
  The mechanisms leading to hypertension associated with hyperuricemia are still unclear. The activity of the distal nephron epithelial sodium channel (ENaC) is an important determinant of sodium balance and blood pressure. Our aim was to investigate whether the effect of hyperuricemia on blood pressure is related to ENaC activation.
  
  
  METHODS
  A hyperuricemic model was induced in rats by 2% oxonic acid and 6 mg/dl uric acid (UA). The hyperuricemic rats were co-treated with either 10mg/kg/d benzbromarone (Ben) or 1 mg/kg/d amiloride (Ami). Blood pressure was monitored using a tail-cuff, and blood, urine, and kidney samples were taken. Western blotting and immunohistochemical staining were performed to determine the expressions of ENaC subunits and components of the ENaC Regulatory Complex (ERC) in kidney tissue or mCCD cells.
  
  
  RESULTS
  Serum uric acid (SUA) was increased 2.5-3.5 times above normal in hyperuricemic rats after 3 weeks and remained at these high levels until 6 weeks. The in vivo rise in SUA was followed by elevated blood pressure, renal tubulointerstitial injury, and increased expressions of ENaC subunits, SGK1, and GILZ1, which were prevented by Ben treatment. The decrease in urinary Na(+) excretion in hyperuricemic rats was blunted by Ami. UA induced the expression of all three ENaC subunits, SGK1, and GILZ1, and increased Na(+) transport in mCCD cells. Phosphorylation of ERK was significantly decreased in both UA-treated mCCD cells and hyperuricemic rat kidney; this effect was prevented by Ben co-treatment.
  
  
  CONCLUSIONS
  Our findings suggest that elevated serum uric acid could induce hypertension by activation of ENaC and regulation of ERC expression.
authors.affiliation: Department of Pathophysiology, Nanjing Medical University, Nanjing, Jiangsu Province, China; Zhuji people Hospital, Zhuji, Zhejiang Province, China.
authors.forename: Weifeng
authors.initials: W
authors.lastname: Xu
authors.affiliation: Department of Pathophysiology, Nanjing Medical University, Nanjing, Jiangsu Province, China.
authors.forename: Yujie
authors.initials: Y
authors.lastname: Huang
authors.affiliation: Department of Pathophysiology, Nanjing Medical University, Nanjing, Jiangsu Province, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Pathophysiology, Nanjing Medical University, Nanjing, Jiangsu Province, China.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Sun
authors.affiliation: Department of Pathophysiology, Nanjing Medical University, Nanjing, Jiangsu Province, China.
authors.forename: Yachen
authors.initials: Y
authors.lastname: Shen
authors.affiliation: Department of Pathophysiology, Nanjing Medical University, Nanjing, Jiangsu Province, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Xing
authors.affiliation: Department of Pathophysiology, Nanjing Medical University, Nanjing, Jiangsu Province, China.
authors.forename: Min
authors.initials: M
authors.lastname: Li
authors.affiliation: Department of Pathology, Nanjing Medical University, Nanjing, Jiangsu Province, China; State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, Jiangsu Province, China.
authors.forename: Dongming
authors.initials: D
authors.lastname: Su
authors.affiliation: Department of Pathophysiology, Nanjing Medical University, Nanjing, Jiangsu Province, China; State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, Jiangsu Province, China. Electronic address: liangxiubin@njmu.edu.cn.
authors.forename: Xiubin
authors.initials: X
authors.lastname: Liang
mesh_terms: D000584:Amiloride / Q000494:pharmacology; D000818:Animals; D001553:Benzbromarone / Q000494:pharmacology; D001794:Blood Pressure; D002460:Cell Line; D004232:Diuretics / Q000494:pharmacology; D053503:Epithelial Sodium Channels / Q000378:metabolism*; D006977:Hypertension, Renal / Q000209:etiology* / Q000473:pathology / Q000503:physiopathology; D033461:Hyperuricemia / Q000150:complications* / Q000473:pathology / Q000503:physiopathology; D017874:Immediate-Early Proteins / Q000378:metabolism; D007668:Kidney / Q000473:pathology / Q000503:physiopathology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D000090204:Mesothelin; D051379:Mice; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012964:Sodium / Q000378:metabolism; D014528:Uricosuric Agents / Q000494:pharmacology; D000099184:Serum-Glucocorticoid Regulated Kinases
chemical_list: D000584:Amiloride; D001553:Benzbromarone; D004232:Diuretics; D053503:Epithelial Sodium Channels; D017874:Immediate-Early Proteins; D000090204:Mesothelin; D017346:Protein Serine-Threonine Kinases; D012964:Sodium; D014528:Uricosuric Agents; D000099184:Serum-Glucocorticoid Regulated Kinases; C000715529:Msln protein, rat
keywords: ENaC regulatory complex; Epithelial sodium channel; Hypertension; Hyperuricemia