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.
Highlights
Hereditary polycystic kidney diseases (PKDs) are characterized by progressive enlargement of countless fluid-filled cysts in the bilateral kidneys, and most cases produce liver cystic disorders
We previously reported that pioglitazone, a peroxisome proliferator activated receptor (PPAR)-c full agonist, ameliorates kidney and liver disease progression in PCK rats, an orthologous model of human autosomal recessive PKD (ARPKD) [14,15,16]
Disorders in PCK rats are characterized by renal cysts derived from collecting ducts, and congenital hepatic fibrosis associated with biliary cysts [14,21,22]
Summary
Hereditary polycystic kidney diseases (PKDs) are characterized by progressive enlargement of countless fluid-filled cysts in the bilateral kidneys, and most cases produce liver cystic disorders. Cyst formation is caused by stimulated proliferation of the renal tubule and hepatic bile duct epithelia, together with secretion of fluid into the cyst cavities. Most cases of ADPKD are diagnosed in adulthood, and end-stage renal disease occurs in 50% of patients [2]. ARPKD is a juvenile type cystic disease with an incidence of 1:20,000 [3] which is caused by the PKHD1 gene. Renal cysts originate from collecting ducts with fibrotic tissue. Liver cysts originate from intrahepatic bile ducts and are connected to the biliary tree, which appears distorted and embedded in abundant fibrotic tissue [4]. Renal insufficiency and end-stage renal disease are remarkable symptoms in neonatal patients, and complications of ductal plate malformation caused by congenital hepatic fibrosis (CHF) are prominent in adult survivors [4]
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