Telmisartan ameliorates fibrocystic liver disease in an orthologous rat model of human autosomal recessive polycystic kidney disease

Daisuke Yoshihara, Masanori Kugita, Mai Sasaki, Shigeo Horie, Koichi Nakanishi, Takaaki Abe, Harold M. Aukema, Tamio Yamaguchi, Shizuko Nagao

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

Human autosomal recessive polycystic kidney disease (ARPKD) produces kidneys which are massively enlarged due to multiple cysts, hypertension, and congenital hepatic fibrosis characterized by dilated bile ducts and portal hypertension. The PCK rat is an orthologous model of human ARPKD with numerous fluid-filled cysts caused by stimulated cellular proliferation in the renal tubules and hepatic bile duct epithelia, with interstitial fibrosis developed in the liver. We previously reported that a peroxisome proliferator activated receptor (PPAR)-γ full agonist ameliorated kidney and liver disease in PCK rats. Telmisartan is an angiotensin receptor blocker (ARB) used widely as an antihypertensive drug and shows partial PPAR-γ agonist activity. It also has nephroprotective activity in diabetes and renal injury and prevents the effects of drug-induced hepatotoxicity and hepatic fibrosis. In the present study, we determined whether telmisartan ameliorates progression of polycystic kidney and fibrocystic liver disease in PCK rats. Five male and 5 female PCK and normal control (+/+) rats were orally administered 3 mg/kg telmisartan or vehicle every day from 4 to 20 weeks of age. Treatment with telmisartan decreased blood pressure in both PCK and +/+ rats. Blood levels of aspartate amino transferase, alanine amino transferase and urea nitrogen were unaffected by telmisartan treatment. There was no effect on kidney disease progression, but liver weight relative to body weight, liver cystic area, hepatic fibrosis index, expression levels of Ki67 and TGF-β, and the number of Ki67- and TGF-β-positive interstitial cells in the liver were significantly decreased in telmisartan-treated PCK rats. Therefore, telmisartan ameliorates congenital hepatic fibrosis in ARPKD, possibly through the inhibition of signaling cascades responsible for cellular proliferation and interstitial fibrosis in PCK rats. The present results support the potential therapeutic use of ARBs for the treatment of fibrocystic liver disease in ARPKD patients.

Original languageEnglish
Article numbere81480
JournalPloS one
Volume8
Issue number12
DOIs
Publication statusPublished - 06-12-2013

Fingerprint

Autosomal Recessive Polycystic Kidney
disease models
liver diseases
Liver
Rats
Liver Diseases
animal models
liver cirrhosis
rats
Fibrosis
liver
Peroxisome Proliferator-Activated Receptors
bile ducts
kidneys
Kidney Diseases
Transferases
kidney diseases
Bile Ducts
fibrosis
Kidney

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Yoshihara, Daisuke ; Kugita, Masanori ; Sasaki, Mai ; Horie, Shigeo ; Nakanishi, Koichi ; Abe, Takaaki ; Aukema, Harold M. ; Yamaguchi, Tamio ; Nagao, Shizuko. / Telmisartan ameliorates fibrocystic liver disease in an orthologous rat model of human autosomal recessive polycystic kidney disease. In: PloS one. 2013 ; Vol. 8, No. 12.
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Telmisartan ameliorates fibrocystic liver disease in an orthologous rat model of human autosomal recessive polycystic kidney disease. / Yoshihara, Daisuke; Kugita, Masanori; Sasaki, Mai; Horie, Shigeo; Nakanishi, Koichi; Abe, Takaaki; Aukema, Harold M.; Yamaguchi, Tamio; Nagao, Shizuko.

In: PloS one, Vol. 8, No. 12, e81480, 06.12.2013.

Research output: Contribution to journalArticle

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T1 - Telmisartan ameliorates fibrocystic liver disease in an orthologous rat model of human autosomal recessive polycystic kidney disease

AU - Yoshihara, Daisuke

AU - Kugita, Masanori

AU - Sasaki, Mai

AU - Horie, Shigeo

AU - Nakanishi, Koichi

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AU - Aukema, Harold M.

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AU - Nagao, Shizuko

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AB - Human autosomal recessive polycystic kidney disease (ARPKD) produces kidneys which are massively enlarged due to multiple cysts, hypertension, and congenital hepatic fibrosis characterized by dilated bile ducts and portal hypertension. The PCK rat is an orthologous model of human ARPKD with numerous fluid-filled cysts caused by stimulated cellular proliferation in the renal tubules and hepatic bile duct epithelia, with interstitial fibrosis developed in the liver. We previously reported that a peroxisome proliferator activated receptor (PPAR)-γ full agonist ameliorated kidney and liver disease in PCK rats. Telmisartan is an angiotensin receptor blocker (ARB) used widely as an antihypertensive drug and shows partial PPAR-γ agonist activity. It also has nephroprotective activity in diabetes and renal injury and prevents the effects of drug-induced hepatotoxicity and hepatic fibrosis. In the present study, we determined whether telmisartan ameliorates progression of polycystic kidney and fibrocystic liver disease in PCK rats. Five male and 5 female PCK and normal control (+/+) rats were orally administered 3 mg/kg telmisartan or vehicle every day from 4 to 20 weeks of age. Treatment with telmisartan decreased blood pressure in both PCK and +/+ rats. Blood levels of aspartate amino transferase, alanine amino transferase and urea nitrogen were unaffected by telmisartan treatment. There was no effect on kidney disease progression, but liver weight relative to body weight, liver cystic area, hepatic fibrosis index, expression levels of Ki67 and TGF-β, and the number of Ki67- and TGF-β-positive interstitial cells in the liver were significantly decreased in telmisartan-treated PCK rats. Therefore, telmisartan ameliorates congenital hepatic fibrosis in ARPKD, possibly through the inhibition of signaling cascades responsible for cellular proliferation and interstitial fibrosis in PCK rats. The present results support the potential therapeutic use of ARBs for the treatment of fibrocystic liver disease in ARPKD patients.

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