Acute cholestatic liver disease protects against glycerol-induced acute renal failure in the rat

Nelson Leung, Anthony J. Croatt, Jill J. Haggard, Joseph Peter Grande, Karl A Nath

Research output: Contribution to journalArticle

41 Citations (Scopus)

Abstract

Background. It is widely held that liver disease predisposes toward acute tubular necrosis. The present study examines the effect of acute cholestatic liver disease on the susceptibility to glycerol-induced acute tubular necrosis in the rat. Methods. Acute cholestatic liver disease was induced by ligation of the common bile duct, while the intramuscular injection of hypertonic glycerol was used to induce acute tubular necrosis. Renal injury was assessed by plasma creatinine concentration and renal histology. An in vitro model of heme protein-induced renal injury (hemoglobin in conjunction with glutathione depletion) was employed to assess the cytoprotective effects of bilirubin. Results. Ligation of the common bile duct markedly reduced acute renal injury that occurs in the glycerol model (7.5 mL/kg body weight), as evidenced by a lower plasma creatinine concentration and less severe renal histologic injury. At a higher dose of glycerol (10 mL/kg body weight), ligation of the common bile duct again reduced renal injury and cumulative mortality that occurs five days after the induction of this model of acute renal failure. These protective effects of ligation of the common bile duct could not be ascribed to less severe muscle injury or red cell damage. Ligation of the common bile duct induced heme oxygenase-1 in the kidney and markedly so in the liver. Inhibition of heme oxygenase significantly attenuated, but did not prevent, the protective effects conferred by ligation of the common bile duct. Bilirubin, in low micromolar concentrations, was cytoprotective against heme protein-induced cell injury in vitro. Conclusions. Ligation of the common bile duct confers resistance to glycerol-induced acute tubular necrosis in the rat, actions that arise, in part, from the induction of heme oxygenase-1 in the kidney and liver. Bilirubin, in micromolar concentrations, protects against heme protein-induced renal injury. Our studies uncover a novel form of acquired resistance to renal injury, occurring, unexpectedly, in the setting of acute cholestatic liver disease. We speculate that such potentially cytoprotective alterations may safeguard the kidney against irreversible functional and structural injury in the hepatorenal syndrome.

Original languageEnglish (US)
Pages (from-to)1047-1057
Number of pages11
JournalKidney International
Volume60
Issue number3
DOIs
StatePublished - 2001

Fingerprint

Acute Kidney Injury
Glycerol
Liver Diseases
Common Bile Duct
Kidney
Ligation
Wounds and Injuries
Hemeproteins
Necrosis
Bilirubin
Heme Oxygenase-1
Creatinine
Body Weight
Hepatorenal Syndrome
Heme Oxygenase (Decyclizing)
Liver
Intramuscular Injections
Disease Susceptibility
Glutathione
Histology

Keywords

  • Bile duct ligation
  • Bilirubin
  • Cytoprotection
  • Heme protein-induced nephrotoxicity
  • Hepatorenal syndrome
  • Renal injury

ASJC Scopus subject areas

  • Nephrology

Cite this

Acute cholestatic liver disease protects against glycerol-induced acute renal failure in the rat. / Leung, Nelson; Croatt, Anthony J.; Haggard, Jill J.; Grande, Joseph Peter; Nath, Karl A.

In: Kidney International, Vol. 60, No. 3, 2001, p. 1047-1057.

Research output: Contribution to journalArticle

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abstract = "Background. It is widely held that liver disease predisposes toward acute tubular necrosis. The present study examines the effect of acute cholestatic liver disease on the susceptibility to glycerol-induced acute tubular necrosis in the rat. Methods. Acute cholestatic liver disease was induced by ligation of the common bile duct, while the intramuscular injection of hypertonic glycerol was used to induce acute tubular necrosis. Renal injury was assessed by plasma creatinine concentration and renal histology. An in vitro model of heme protein-induced renal injury (hemoglobin in conjunction with glutathione depletion) was employed to assess the cytoprotective effects of bilirubin. Results. Ligation of the common bile duct markedly reduced acute renal injury that occurs in the glycerol model (7.5 mL/kg body weight), as evidenced by a lower plasma creatinine concentration and less severe renal histologic injury. At a higher dose of glycerol (10 mL/kg body weight), ligation of the common bile duct again reduced renal injury and cumulative mortality that occurs five days after the induction of this model of acute renal failure. These protective effects of ligation of the common bile duct could not be ascribed to less severe muscle injury or red cell damage. Ligation of the common bile duct induced heme oxygenase-1 in the kidney and markedly so in the liver. Inhibition of heme oxygenase significantly attenuated, but did not prevent, the protective effects conferred by ligation of the common bile duct. Bilirubin, in low micromolar concentrations, was cytoprotective against heme protein-induced cell injury in vitro. Conclusions. Ligation of the common bile duct confers resistance to glycerol-induced acute tubular necrosis in the rat, actions that arise, in part, from the induction of heme oxygenase-1 in the kidney and liver. Bilirubin, in micromolar concentrations, protects against heme protein-induced renal injury. Our studies uncover a novel form of acquired resistance to renal injury, occurring, unexpectedly, in the setting of acute cholestatic liver disease. We speculate that such potentially cytoprotective alterations may safeguard the kidney against irreversible functional and structural injury in the hepatorenal syndrome.",
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T1 - Acute cholestatic liver disease protects against glycerol-induced acute renal failure in the rat

AU - Leung, Nelson

AU - Croatt, Anthony J.

AU - Haggard, Jill J.

AU - Grande, Joseph Peter

AU - Nath, Karl A

PY - 2001

Y1 - 2001

N2 - Background. It is widely held that liver disease predisposes toward acute tubular necrosis. The present study examines the effect of acute cholestatic liver disease on the susceptibility to glycerol-induced acute tubular necrosis in the rat. Methods. Acute cholestatic liver disease was induced by ligation of the common bile duct, while the intramuscular injection of hypertonic glycerol was used to induce acute tubular necrosis. Renal injury was assessed by plasma creatinine concentration and renal histology. An in vitro model of heme protein-induced renal injury (hemoglobin in conjunction with glutathione depletion) was employed to assess the cytoprotective effects of bilirubin. Results. Ligation of the common bile duct markedly reduced acute renal injury that occurs in the glycerol model (7.5 mL/kg body weight), as evidenced by a lower plasma creatinine concentration and less severe renal histologic injury. At a higher dose of glycerol (10 mL/kg body weight), ligation of the common bile duct again reduced renal injury and cumulative mortality that occurs five days after the induction of this model of acute renal failure. These protective effects of ligation of the common bile duct could not be ascribed to less severe muscle injury or red cell damage. Ligation of the common bile duct induced heme oxygenase-1 in the kidney and markedly so in the liver. Inhibition of heme oxygenase significantly attenuated, but did not prevent, the protective effects conferred by ligation of the common bile duct. Bilirubin, in low micromolar concentrations, was cytoprotective against heme protein-induced cell injury in vitro. Conclusions. Ligation of the common bile duct confers resistance to glycerol-induced acute tubular necrosis in the rat, actions that arise, in part, from the induction of heme oxygenase-1 in the kidney and liver. Bilirubin, in micromolar concentrations, protects against heme protein-induced renal injury. Our studies uncover a novel form of acquired resistance to renal injury, occurring, unexpectedly, in the setting of acute cholestatic liver disease. We speculate that such potentially cytoprotective alterations may safeguard the kidney against irreversible functional and structural injury in the hepatorenal syndrome.

AB - Background. It is widely held that liver disease predisposes toward acute tubular necrosis. The present study examines the effect of acute cholestatic liver disease on the susceptibility to glycerol-induced acute tubular necrosis in the rat. Methods. Acute cholestatic liver disease was induced by ligation of the common bile duct, while the intramuscular injection of hypertonic glycerol was used to induce acute tubular necrosis. Renal injury was assessed by plasma creatinine concentration and renal histology. An in vitro model of heme protein-induced renal injury (hemoglobin in conjunction with glutathione depletion) was employed to assess the cytoprotective effects of bilirubin. Results. Ligation of the common bile duct markedly reduced acute renal injury that occurs in the glycerol model (7.5 mL/kg body weight), as evidenced by a lower plasma creatinine concentration and less severe renal histologic injury. At a higher dose of glycerol (10 mL/kg body weight), ligation of the common bile duct again reduced renal injury and cumulative mortality that occurs five days after the induction of this model of acute renal failure. These protective effects of ligation of the common bile duct could not be ascribed to less severe muscle injury or red cell damage. Ligation of the common bile duct induced heme oxygenase-1 in the kidney and markedly so in the liver. Inhibition of heme oxygenase significantly attenuated, but did not prevent, the protective effects conferred by ligation of the common bile duct. Bilirubin, in low micromolar concentrations, was cytoprotective against heme protein-induced cell injury in vitro. Conclusions. Ligation of the common bile duct confers resistance to glycerol-induced acute tubular necrosis in the rat, actions that arise, in part, from the induction of heme oxygenase-1 in the kidney and liver. Bilirubin, in micromolar concentrations, protects against heme protein-induced renal injury. Our studies uncover a novel form of acquired resistance to renal injury, occurring, unexpectedly, in the setting of acute cholestatic liver disease. We speculate that such potentially cytoprotective alterations may safeguard the kidney against irreversible functional and structural injury in the hepatorenal syndrome.

KW - Bile duct ligation

KW - Bilirubin

KW - Cytoprotection

KW - Heme protein-induced nephrotoxicity

KW - Hepatorenal syndrome

KW - Renal injury

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