Collagen-driven remodeling of the intrahepatic duct wall in the PCK rat model of polycystic kidney disease-Caroli syndrome

Abstract

Aim of the study Autosomal dominant polycystic kidney disease (ADPKD) is characterized by formation and expansion of cysts within the kidney. Caroli syndrome (CS) is characterized by cystic saccular dilatation of intrahepatic ducts. Kidney and liver images from a model of ADPKD-CS were evaluated to characterize remodeling of the cystically dilated intrahepatic duct wall and the renal cyst wall. Material and methods Archival digitized images from Masson’s trichrome-stained renal and Picrosirius red (PSR)-stained renal and hepatic cross-sections were sourced from the PCK rat model of ADPKD-CS, and age-matched Sprague-Dawley rats (wild-type). Cross-sectional areas and wall thicknesses of renal cysts and intrahepatic ducts were measured. Circularly polarized PSR microscopy was utilized to observe accumulation of collagen and identify its subtype. Results In the PCK rat model of ADPKD-CS, renal cysts were relatively thin-walled in comparison to intrahepatic ducts with renal cyst cross-sectional area to wall ratio 47-fold greater than the corresponding ratio in intrahepatic ducts. Increasing intrahepatic duct cross-sectional area was accompanied by a rapid and steep rise in wall thickness. There was a weak but significant direct correlation ( r = 0.49, p = 0.037) between renal cyst cross-sectional area and wall thickness. Circularly polarized Picrosirius red microscopy revealed collagen I accumulation within the walls of dilated intrahepatic ducts but not renal cysts. Conclusions These data suggest that unlike renal cysts, cystically dilated intrahepatic ducts undergo collagen-driven wall remodeling in the PCK rat.

Liver Biopsy Hydroxyproline Content Is a Diagnostic for Hepatocellular Carcinoma in Murine Models of Nonalcoholic Steatohepatitis

“…Hydroxyproline, a major component of collagen, can be assayed biochemically, is not subject to observer bias and is routinely assayed to estimate liver fibrosis [ 3 , 14 , 15 ]. There is also evidence to suggest that excessive collagen deposition is associated with the transformation of the scarred liver an oncological phenotype [ 3 , 16 , 17 ]. Liver hydroxyproline content was evaluated in murine models of NASH with or without HCC.…”

“…Liver hydroxyproline content was evaluated in murine models of NASH with or without HCC. Disease was induced in mice with the administration of a modified diet or the modified diet with chemicals, both of which have been reported to demonstrate the entire spectrum of NAFLD culminating in HCC [ 3 , 15 , 17 , 18 , 19 , 20 ].…”

Collagen Characterization in a Model of Nonalcoholic Steatohepatitis with Fibrosis; A Call for Development of Targeted Therapeutics

“…Circular polarized PSR microscopy was used to determine the nature of any deposited COL. Bright field images showed characteristic PSR staining in the FFD cohort but not in the sham cohort while under polarized light, in the FFD cohort, PSR staining appeared bright yellow-orange, indicative of COL I deposition ( Figure 4 ) [ 21 , 22 ].…”

“…Relatively inexpensive, the technique relies on the birefringent properties of collagen molecules. While the PSR stain alone does not selectively bind the collagen network, it becomes more specific than the other common collagen stains when combined with polarized light detection [ 21 , 22 ]. Under circularly polarized PSR microscopy, thin bundles of collagen type III appear yellow-green, whereas large bundles of tightly packed, well-organized, and mature collagen type I molecules appear yellow-orange [ 21 ].…”

“…Circularly polarized PSR microscopy [ 22 , 28 ] was utilized to observe accumulation of COL and identify its subtype based on the birefringence pattern. Under polarized light, COL I fibers appear yellow-orange and COL III fibers appear yellow-green.…”