Renin-angiotensin system activation in congenital hepatic fibrosis in the PCK rat model of autosomal recessive polycystic kidney disease

The present study demonstrates, for the first time, RAS upregulation in an orthologous rat ARPKD/CHF model. Increases in ACE and ANG II, as well as the downstream target, the profibrotic mediator TGF-beta, suggest that RAS activation may be an important mediator of CHF disease progression. The findings also suggest that treatment with RAS inhibitors, specifically ACE inhibitors or AT1R blockers, could be therapeutic in slowing disease progression in CHF.

Studies were conducted in the PCK rat, an orthologous ARPKD/CHF model, and age-matched normal control Sprague-Dawley rats. Expression of the RAS components, renin, angiotensinogen, angiotensin-converting enzyme (ACE), and angiotensin II type 1 receptor (AT1R), as well as the profibrotic mediator TGF-beta, was examined in cystic PCK and control rat livers at 2, 4, and 6 months of age by quantitative real-time polymerase chain reaction (qRT-PCR). Angiotensin II (ANG II) was examined by immunohistochemistry (IHC). Fibrosis was assessed by IHC using reticulin staining and Masson trichrome. Collagen content was determined by hydroxyproline analysis.

Progressive fibrosis and increased hepatic collagen content occurred in PCK rats with age. In 4- and 6-month-old PCK rat livers, ACE gene expression was markedly increased, 8- and 17-fold, respectively, compared with age-matched control livers. Expression of the other RAS components, renin, angiotensinogen, and AT1R were not significantly different. IHC demonstrated prominent ANG II protein expression in periportal regions in PCK rats. In contrast, no expression was noted in control livers. TGF-beta expression was also increased in PCK rat livers with progressive disease. Conclusions: The present study demonstrates, for the first time, RAS upregulation in an orthologous rat ARPKD/CHF model. Increases in ACE and ANG II, as well as the downstream target, the profibrotic mediator TGF-beta, suggest that RAS activation may be an important mediator of CHF disease progression. The findings also suggest that treatment with RAS inhibitors, specifically ACE inhibitors or AT1R blockers, could be therapeutic in slowing disease progression in CHF.