Four‐jointed knock‐out delays renal failure in an ADPKD model with kidney injury

• Published in: The Journal of pathology Vol. 249; no. 1; pp. 114 - 125
• Main Authors: Formica, Chiara, Happé, Hester, Veraar, Kimberley AM, Vortkamp, Andrea, Scharpfenecker, Marion, McNeill, Helen, Peters, Dorien JM
• Format: Journal Article
• Language: English
• Published: Chichester, UK John Wiley & Sons, Ltd 01-09-2019; Wiley Subscription Services, Inc
• Subjects: Acute Kidney Injury - chemically induced; Acute Kidney Injury - complications; Acute Kidney Injury - genetics; Acute Kidney Injury - metabolism; ADPKD; Animals; cell polarity; Clonal deletion; Cysteine - analogs & derivatives; Cysts; Disease Models, Animal; Disease Progression; Disruption; Fibrosis; Inflammation Mediators - metabolism; Intercellular Signaling Peptides and Proteins - deficiency; Intercellular Signaling Peptides and Proteins - genetics; Kidney - metabolism; Kidney - pathology; Kidney diseases; Kidney Failure, Chronic - etiology; Kidney Failure, Chronic - genetics; Kidney Failure, Chronic - metabolism; kidney injury; Kidneys; Macrophages; Male; Mice; Mice, Knockout; Mutation; Original Paper; Original Papers; Polarity; Polycystic kidney; Polycystic kidney disease 1 protein; Polycystic Kidney, Autosomal Dominant - complications; Polycystic Kidney, Autosomal Dominant - genetics; Polycystic Kidney, Autosomal Dominant - metabolism; Renal failure; Rodents; Time Factors; TRPP Cation Channels - genetics; Wnt Signaling Pathway; ADPKD; fibrosis; cell polarity; kidney injury
• ISSN: 0022-3417; 1096-9896
• DOI: 10.1002/path.5286

Autosomal Dominant Polycystic Kidney Disease is characterised by the development of fluid‐filled cysts in the kidneys which lead to end‐stage renal disease (ESRD). In the majority of cases, the disease is caused by a mutation in the Pkd1 gene. In a previous study, we demonstrated that renal injury can accelerate cyst formation in Pkd1 knock‐out (KO) mice. In that study, we found that after injury four‐jointed (Fjx1), an upstream regulator of planar cell polarity and the Hippo pathway, was aberrantly expressed in Pkd1 KO mice compared to WT. Therefore, we hypothesised a role for Fjx1 in injury/repair and cyst formation. We generated single and double deletion mice for Pkd1 and Fjx1, and we induced toxic renal injury using the nephrotoxic compound 1,2‐dichlorovinyl‐cysteine. We confirmed that nephrotoxic injury can accelerate cyst formation in Pkd1 mutant mice. This caused Pkd1 KO mice to reach ESRD significantly faster; unexpectedly, double KO mice survived significantly longer. Cyst formation was comparable in both models, but we found significantly less fibrosis and macrophage infiltration in double KO mice. Taken together, these data suggest that Fjx1 disruption protects the cystic kidneys against kidney failure by reducing inflammation and fibrosis. Moreover, we describe, for the first time, an interesting (yet unidentified) mechanism that partially discriminates cyst growth from fibrogenesis. © 2019 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.