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

Marion Scharpfenecker,Andrea Vortkamp,Kimberley AM Veraar,Dorien JM Peters,Hester Happé,Helen McNeill,Chiara Formica

doi:10.1002/path.5286

Abstract

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.

Highlights

Autosomal Dominant Polycystic Kidney Disease (ADPKD) is a genetic disease caused in the majority of the cases by a mutation in the PKD1 gene, which encodes polycystin 1, and in the remaining cases by a mutation in the PKD2 gene, encoding polycystin 2 [1]
In this study we showed that nephrotoxic injury can accelerate disease progression in Pkd1 KO mice but that this effect is abolished in the absence of four-jointed box kinase 1 (Fjx1) expression, allowing the Pkd1/Fjx1 double KO mice to survive on average 5 weeks longer than the single Pkd1 KO mice
At 10 weeks after DCVC and kidney failure, we observed a reduction in injury marker expression together with reduced fibrosis and macrophage infiltration in Pkd1 KO mice compared with double KO

Summary

Introduction

Autosomal Dominant Polycystic Kidney Disease (ADPKD) is a genetic disease caused in the majority of the cases by a mutation in the PKD1 gene, which encodes polycystin 1, and in the remaining cases by a mutation in the PKD2 gene, encoding polycystin 2 [1]. The hallmark of this disease is the formation of fluid-filled cysts in the kidneys, which grow slowly and progressively disrupt the renal parenchyma, leading to kidney failure [1,2]. Fjx is implicated with two important pathways normally aberrant in ADPKD: planar cell polarity (PCP) and the Hippo pathway

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