Endotoxemia-enhanced renal vascular reactivity to endothelin-1 in cirrhotic rats

Chiao Lin Chuang, Ching Chih Chang, Shao Jung Hsu, Hui Chun Huang*, Fa Yauh Lee, Ling Ju Huang, Shou Dong Lee

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

7 Scopus citations

Abstract

Hepatorenal syndrome (HRS), a severe complication of advanced cirrhosis, is defined as hypoperfusion of kidneys resulting from intense renal vasoconstriction in response to generalized systemic arterial vasodilatation. Nevertheless, the mechanisms have been barely investigated. Cumulative studies demonstrated renal vasodilatation in portal hypertensive and compensated cirrhotic rats. Previously, we identified that blunted renal vascular reactivity of portal hypertensive rats was reversed after lipopolysaccharide (LPS). This study was therefore conducted to delineate the sequence of renal vascular alternation and underlying mechanisms in LPS-treated cirrhotic rats. Sprague-Dawley rats were randomly allocated to receive sham surgery (Sham) or common bile duct ligation (CBDL). LPS was induced on the 28th day after surgery. Kidney perfusion was performed at 0.5 or 3 h after LPS to evaluate renal vascular response to endothelin-1 (ET-1). Endotoxemia increased serum ET-1 levels (P < 0.0001) and renal arterial blood flow (P < 0.05) in both Sham and CBDL rats. CBDL rats showed enhanced renal vascular reactivity to ET-1 at 3 h after LPS (P = 0.026). Pretreatment with endothelin receptor type A (ET A ) antagonist abrogated the LPS-enhanced renal vascular response in CBDL rats (P < 0.001). There were significantly lower inducible nitric oxide synthase (iNOS) expression but higher ET A and phosphorylated extracellular signal-regulated kinase (p-ERK) expressions in renal medulla of endotoxemic CBDL rats (P < 0.05). We concluded that LPS-induced renal iNOS inhibition, ET A upregulation, and subsequent ERK signaling activation may participate in renal vascular hyperreactivity in cirrhosis. ET-1-targeted therapy may be feasible in the control of HRS.

Original languageEnglish
Pages (from-to)G752-G761
JournalAmerican Journal of Physiology - Gastrointestinal and Liver Physiology
Volume315
Issue number5
DOIs
StatePublished - Nov 2018

Keywords

  • Cirrhosis
  • Endothelin receptor type A
  • Endothelin-1
  • Lipopolysaccharide
  • Renal vascular reactivity

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