Renal Ciliopathies: Sorting Out Therapeutic Approaches for Nephronophthisis.

Marijn F Stokman,Sophie Saunier,Alexandre Benmerah

doi:10.3389/fcell.2021.653138

Abstract

Nephronophthisis (NPH) is an autosomal recessive ciliopathy and a major cause of end-stage renal disease in children. The main forms, juvenile and adult NPH, are characterized by tubulointerstitial fibrosis whereas the infantile form is more severe and characterized by cysts. NPH is caused by mutations in over 20 different genes, most of which encode components of the primary cilium, an organelle in which important cellular signaling pathways converge. Ciliary signal transduction plays a critical role in kidney development and tissue homeostasis, and disruption of ciliary signaling has been associated with cyst formation, epithelial cell dedifferentiation and kidney function decline. Drugs have been identified that target specific signaling pathways (for example cAMP/PKA, Hedgehog, and mTOR pathways) and rescue NPH phenotypes in in vitro and/or in vivo models. Despite identification of numerous candidate drugs in rodent models, there has been a lack of clinical trials and there is currently no therapy that halts disease progression in NPH patients. This review covers the most important findings of therapeutic approaches in NPH model systems to date, including hypothesis-driven therapies and untargeted drug screens, approached from the pathophysiology of NPH. Importantly, most animal models used in these studies represent the cystic infantile form of NPH, which is less prevalent than the juvenile form. It appears therefore important to develop new models relevant for juvenile/adult NPH. Alternative non-orthologous animal models and developments in patient-based in vitro model systems are discussed, as well as future directions in personalized therapy for NPH.

Highlights

Nephronophthisis (NPH) is an autosomal recessive kidney disease that accounts for up to 15% of end-stage renal disease (ESRD) in children (Hamiwka et al, 2008; Salomon et al, 2009)
Autosomal dominant polycystic kidney disease (ADPKD), which is more prevalent, is typically adult-onset with slow progression to ESRD [onset from 58 to 80 years (Chebib and Torres, 2016)] and characterized by enlarged kidneys with cysts distributed throughout the renal parenchyma (Harris and Torres, 2002)
In this review we summarize the results from two main strategies for therapeutic intervention in NPH that have been investigated in in vitro and in vivo model systems: pharmacotherapy and gene-based therapy, in relation to the pathophysiology of different aspects of the NPH phenotype

Summary

Introduction

Nephronophthisis (NPH) is an autosomal recessive kidney disease that accounts for up to 15% of end-stage renal disease (ESRD) in children (Hamiwka et al, 2008; Salomon et al, 2009). Juvenile NPH is characterized by small to normal-sized kidneys that show marked tubulointerstitial fibrosis, thickened and disrupted tubular basement membranes and, in less than 50% of patients, corticomedullary cysts that arise from distal tubules in advanced stages of the disease (Hildebrandt et al, 2009). A recent study described a hypomorphic mutation in tmem67 (NPHP11), leading to ciliary defects and tubular cysts in adult zebrafish kidneys (Zhu et al, 2021), indicating that such models can be generated.

Results

Conclusion