title: Evidence for a "Pathogenic Triumvirate" in Congenital Hepatic Fibrosis in Autosomal Recessive Polycystic Kidney Disease.
abstract: Autosomal recessive polycystic kidney disease (ARPKD) is a severe monogenic disorder that occurs due to mutations in thePKHD1gene. Congenital hepatic fibrosis (CHF) associated with ARPKD is characterized by the presence of hepatic cysts derived from dilated bile ducts and a robust, pericystic fibrosis. Cyst growth, due to cyst wall epithelial cell hyperproliferation and fluid secretion, is thought to be the driving force behind disease progression. Liver fibrosis is a wound healing response in which collagen accumulates in the liver due to an imbalance between extracellular matrix synthesis and degradation. Whereas both hyperproliferation and pericystic fibrosis are hallmarks of CHF/ARPKD, whether or not these two processes influence one another remains unclear. Additionally, recent studies demonstrate that inflammation is a common feature of CHF/ARPKD. Therefore, we propose a "pathogenic triumvirate" consisting of hyperproliferation of cyst wall growth, pericystic fibrosis, and inflammation which drives CHF/ARPKD progression. This review will summarize what is known regarding the mechanisms of cyst growth, fibrosis, and inflammation in CHF/ARPKD. Further, we will discuss the potential advantage of identifying a core pathogenic feature in CHF/ARPKD to aid in the development of novel therapeutic approaches. If a core pathogenic feature does not exist, then developing multimodality therapeutic approaches to target each member of the "pathogenic triumvirate" individually may be a better strategy to manage this debilitating disease.
authors.affiliation: Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, 3901 Rainbow Blvd, Kansas City, KS 66160, USA.
authors.forename: Lu
authors.identifier: 0000-0001-9619-8311
authors.initials: L
authors.lastname: Jiang
authors.affiliation: Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, 3901 Rainbow Blvd, Kansas City, KS 66160, USA.
authors.forename: Pingping
authors.initials: P
authors.lastname: Fang
authors.affiliation: Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, 3901 Rainbow Blvd, Kansas City, KS 66160, USA.
authors.forename: James L
authors.initials: JL
authors.lastname: Weemhoff
authors.affiliation: Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, 3901 Rainbow Blvd, Kansas City, KS 66160, USA.
authors.forename: Udayan
authors.initials: U
authors.lastname: Apte
authors.affiliation: Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, 3901 Rainbow Blvd, Kansas City, KS 66160, USA.
authors.forename: Michele T
authors.identifier: 0000-0002-0095-0685
authors.initials: MT
authors.lastname: Pritchard
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D030342:Genetic Diseases, Inborn / Q000150:complications* / Q000473:pathology* / Q000628:therapy; D006801:Humans; D007249:Inflammation / Q000150:complications / Q000473:pathology; D008103:Liver Cirrhosis / Q000150:complications* / Q000473:pathology* / Q000628:therapy; D017044:Polycystic Kidney, Autosomal Recessive / Q000150:complications* / Q000235:genetics / Q000473:pathology* / Q000628:therapy