Disease Modeling To Understand the Pathomechanisms of Human Genetic Kidney Disorders

Abstract

The class of human genetic kidney diseases is extremely broad and heterogeneous. Accordingly, the range of associated disease phenotypes is highly variable. Many children and adults affected by inherited kidney disease will progress to ESKD at some point in life. Extensive research has been performed on various different disease models to investigate the underlying causes of genetic kidney disease and to identify disease mechanisms that are amenable to therapy. We review some of the research highlights that, by modeling inherited kidney disease, contributed to a better understanding of the underlying pathomechanisms, leading to the identification of novel genetic causes, new therapeutic targets, and to the development of new treatments. We also discuss how the implementation of more efficient genome-editing techniques and tissue-culture methods for kidney research is providing us with personalized models for a precision-medicine approach that takes into account the specificities of the patient and the underlying disease. We focus on the most common model systems used in kidney research and discuss how, according to their specific features, they can differentially contribute to biomedical research. Unfortunately, no definitive treatment exists for most inherited kidney disorders, warranting further exploitation of the existing disease models, as well as the implementation of novel, complex, human patient–specific models to deliver research breakthroughs.

Organs-on-chip technology: a tool to tackle genetic kidney diseases

“…Several disease models (animal and cellular) for inherited kidney diseases have been developed to identify aberrant pathways and novel therapeutic targets, or as drug screening and testing platforms [ 4 ]. Deviating from animal models that are unable to fully recapitulate human pathophysiology, human models are becoming highly appealing [ 13 ].…”

“…A plethora of disease models, ranging from zebrafish and C. elegans to rodents and in vitro patient-derived cell culturing, have contributed to the identification of novel genetic causes, new therapeutic targets, and to the development of new treatments. For a better overview of these models, we guide the reader to the work of Molinari et al [ 4 ].…”

Zebrafish for Personalized Regenerative Medicine; A More Predictive Humanized Model of Endocrine Disease

“…Eventually, regarding the genetically tractable characteristics of zebrafish, it can be developed into a transgenic model as one of the strategies of its application in personalized medicine in different fields of human diseases ( 3 , 63 , 69 ). Since many kidney diseases are caused by mono/polygenic mutations, zebrafish is used to both reveal the underlying genetic mutation and pathophysiology and model for drug screening in the hopes of personalized medicine) ( 71 – 73 ). On the other hand, zebrafish is distinctly useful in personalized medicine when treatment options are abundant, etiologies are not well-established, or the abnormality is rare; like endocrine disorders, cancers, and Duchene muscular dystrophy ( 11 , 74 , 75 ).…”

Interpreting the pathogenicity of Joubert Syndrome missense variants inCaenorhabditis elegans

“…Caenorhabditis elegans , where cilia are found at the ends of the dendrites of 60 sensory neurons (Inglis et al, 2007) . Many ciliopathy proteins and associated pathways are conserved in the worm (Kim et al, 2018;van Dam et al, 2019) , and C. elegans studies have led to seminal discoveries that have greatly instructed our understanding of cilia biology in vertebrates and mammals (Blacque & Sanders, 2014;Ganner & Neumann-Haefelin, 2017;Mok & Héon, 2012;Molinari & Sayer, 2020) . Genetic studies in C. elegans have revealed that TZ proteins function within two distinct entities termed the 'NPHP' and 'MKS' modules (Williams et al, 2008(Williams et al, , 2011 .…”