scholarly journals Disease Modeling To Understand the Pathomechanisms of Human Genetic Kidney Disorders

2020 ◽  
Vol 15 (6) ◽  
pp. 855-872 ◽  
Author(s):  
Elisa Molinari ◽  
John A. Sayer
Keyword(s):  
Kidney Disease ◽  
Disease Modeling ◽  
Kidney Diseases ◽  
Model Systems ◽  
Definitive Treatment ◽  
Patient Specific ◽  
Disease Models ◽  
Culture Methods ◽  
Human Patient ◽  
Inherited Kidney Disease

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.

scholarly journals APOL1 polymorphisms and kidney disease: loss-of-function or gain-of-function?

2019 ◽  
Vol 316 (1) ◽  
pp. F1-F8 ◽  
Author(s):  
Leslie A. Bruggeman ◽  
John F. O’Toole ◽  
John R. Sedor
Keyword(s):  
Kidney Disease ◽  
Human Genetics ◽  
Disease Risk ◽  
Kidney Diseases ◽  
Expression Patterns ◽  
Model Systems ◽  
Recessive Trait ◽  
Loss Of Function ◽  
Allele Expression ◽  
Basic Biology

The mechanism that explains the association of APOL1 variants with nondiabetic kidney diseases in African Americans remains unclear. Kidney disease risk is inherited as a recessive trait, and many studies investigating the intracellular function of APOL1 have indicated the APOL1 variants G1 and G2 are associated with cytotoxicity. Whether cytotoxicity results from the absence of a protective effect conferred by the G0 allele or is induced by a deleterious effect of variant allele expression has not be conclusively established. A central issue hampering basic biology studies is the lack of model systems that authentically replicate APOL1 expression patterns. APOL1 is present in humans and a few other primates and appears to have important functions in the kidney, as the kidney is the primary target for disease associated with the genetic variance. There have been no studies to date assessing the function of untagged APOL1 protein under native expression in human or primate kidney cells, and no studies have examined the heterozygous state, a disease-free condition in humans. A second major issue is the chronic kidney disease (CKD)-associated APOL1 variants are conditional mutations, where the disease-inducing function is only evident under the appropriate environmental stimulus. In addition, it is possible there may be more than one mechanism of pathogenesis that is dependent on the nature of the stressor or other genetic variabilities. Studies addressing the function of APOL1 and how the CKD-associated APOL1 variants cause kidney disease are challenging and remain to be fully investigated under conditions that faithfully model known human genetics and physiology.

scholarly journals Kidney Organoid and Microphysiological Kidney Chip Models to Accelerate Drug Development and Reduce Animal Testing

2021 ◽  
Vol 12 ◽  
Author(s):  
Wei-Yang Chen ◽  
Eric A Evangelista ◽  
Jade Yang ◽  
Edward J Kelly ◽  
Catherine K Yeung
Keyword(s):  
Cell Culture ◽  
Kidney Disease ◽  
Drug Development ◽  
Disease Modeling ◽  
Kidney Diseases ◽  
Three Dimensional ◽  
New Drugs ◽  
Electrolyte Balance ◽  
Animal Testing ◽  
Drug Induced

Kidneys are critical for the elimination of many drugs and metabolites via the urine, filtering waste and maintaining proper fluid and electrolyte balance. Emerging technologies incorporating engineered three-dimensional (3D) in vitro cell culture models, such as organoids and microphysiological systems (MPS) culture platforms, have been developed to replicate nephron function, leading to enhanced efficacy, safety, and toxicity evaluation of new drugs and environmental exposures. Organoids are tiny, self-organized three-dimensional tissue cultures derived from stem cells that can include dozens of cell types to replicate the complexity of an organ. In contrast, MPS are highly controlled fluidic culture systems consisting of isolated cell type(s) that can be used to deconvolute mechanism and pathophysiology. Both systems, having their own unique benefits and disadvantages, have exciting applications in the field of kidney disease modeling and therapeutic discovery and toxicology. In this review, we discuss current uses of both hPSC-derived organoids and MPS as pre-clinical models for studying kidney diseases and drug induced nephrotoxicity. Examples such as the use of organoids to model autosomal dominant polycystic kidney disease, and the use of MPS to predict renal clearance and nephrotoxic concentrations of novel drugs are briefly discussed. Taken together, these novel platforms allow investigators to elaborate critical scientific questions. While much work needs to be done, utility of these 3D cell culture technologies has an optimistic outlook and the potential to accelerate drug development while reducing the use of animal testing.

scholarly journals Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes Afford New Opportunities in Inherited Cardiovascular Disease Modeling

2016 ◽  
Vol 2016 ◽  
pp. 1-17 ◽  
Author(s):  
Daniel R. Bayzigitov ◽  
Sergey P. Medvedev ◽  
Elena V. Dementyeva ◽  
Sevda A. Bayramova ◽  
Evgeny A. Pokushalov ◽  
...  
Keyword(s):  
Cardiovascular Disease ◽  
Stem Cell ◽  
Pluripotent Stem Cell ◽  
Molecular Mechanisms ◽  
Disease Modeling ◽  
Induced Pluripotent Stem Cell ◽  
Model Systems ◽  
Laboratory Animals ◽  
Patient Specific ◽  
Induced Pluripotent

Fundamental studies of molecular and cellular mechanisms of cardiovascular disease pathogenesis are required to create more effective and safer methods of their therapy. The studies can be carried out only when model systems that fully recapitulate pathological phenotype seen in patients are used. Application of laboratory animals for cardiovascular disease modeling is limited because of physiological differences with humans. Since discovery of induced pluripotency generating induced pluripotent stem cells has become a breakthrough technology in human disease modeling. In this review, we discuss a progress that has been made in modeling inherited arrhythmias and cardiomyopathies, studying molecular mechanisms of the diseases, and searching for and testing drug compounds using patient-specific induced pluripotent stem cell-derived cardiomyocytes.

scholarly journals Engineering functional human gastrointestinal organoid tissues using the three primary germ layers separately derived from pluripotent stem cells

2021 ◽  
Author(s):  
Alexandra K Eicher ◽  
Daniel O Kechele ◽  
Nambirajan Sundaram ◽  
H Matthew Berns ◽  
Holly M Poling ◽  
...  
Keyword(s):  
Stem Cells ◽  
Pluripotent Stem Cells ◽  
Disease Modeling ◽  
Clinical Care ◽  
Regional Identity ◽  
Model Systems ◽  
Gastric Epithelium ◽  
Enteric Neurons ◽  
Patient Specific ◽  
Germ Layers

The development of human organoid model systems has provided new avenues for patient-specific clinical care and disease modeling. However, all organoid systems are missing important cell types that, in the embryo, get incorporated into organ tissues during development. Based on the concept of how embryonic organs are assembled, we developed an organoid assembly approach starting with cells from the three primary germ layers; enteric neuroglial, mesenchymal, and epithelial precursors, all separately derived from human pluripotent stem cells. From these we generated human gastric tissue containing differentiated glands, surrounded by layers of smooth muscle containing functional enteric neurons that controlled contractions of the engineered tissue. We used this highly tractable system to identify essential roles for the enteric nervous system in the growth and regional identity of the gastric epithelium and mesenchyme and for glandular morphogenesis of the antral stomach. This approach of starting with separately-derived germ layer components was applied to building more complex fundic and esophageal tissue, suggesting this as a new paradigm for tissue engineering.

scholarly journals Evaluation of endogenous miRNA reference genes across different zebrafish strains, developmental stages and kidney disease models

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Florian Siegerist ◽  
Tim Lange ◽  
Anna Iervolino ◽  
Thor Magnus Koppe ◽  
Weibin Zhou ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Reference Genes ◽  
Developmental Stages ◽  
Kidney Diseases ◽  
Morphological Changes ◽  
Group Differences ◽  
Disease Models ◽  
Endogenous Reference ◽  
Process Architecture

AbstractThe majority of kidney diseases arise from the loss of podocytes and from morphological changes of their highly complex foot process architecture, which inevitably leads to a reduced kidney filtration and total loss of kidney function. It could have been shown that microRNAs (miRs) play a pivotal role in the pathogenesis of podocyte-associated kidney diseases. Due to their fully functioning pronephric kidney, larval zebrafish have become a popular vertebrate model, to study kidney diseases in vivo. Unfortunately, there is no consensus about a proper normalization strategy of RT-qPCR-based miRNA expression data in zebrafish. In this study we analyzed 9 preselected candidates dre-miR-92a-3p, dre-miR-206-3p, dre-miR-99-1, dre-miR-92b-3p, dre-miR-363-3p, dre-let-7e, dre-miR-454a, dre-miR-30c-5p, dre-miR-126a-5p for their capability as endogenous reference genes in zebrafish experiments. Expression levels of potential candidates were measured in 3 different zebrafish strains, different developmental stages, and in different kidney disease models by RT-qPCR. Expression values were analyzed with NormFinder, BestKeeper, GeNorm, and DeltaCt and were tested for inter-group differences. All candidates show an abundant expression throughout all samples and relatively high stability. The most stable candidate without significant inter-group differences was dre-miR-92b-3p making it a suitable endogenous reference gene for RT-qPCR-based miR expression zebrafish studies.

scholarly journals Targeting STAT3 signaling in kidney disease

2019 ◽  
Vol 316 (6) ◽  
pp. F1151-F1161 ◽  
Author(s):  
Jesse Pace ◽  
Praharshasai Paladugu ◽  
Bhaskar Das ◽  
John C. He ◽  
Sandeep K. Mallipattu
Keyword(s):  
Kidney Disease ◽  
Kidney Diseases ◽  
Janus Kinase ◽  
Disease Models ◽  
Pharmacological Inhibition ◽  
Stat3 Signaling ◽  
Stat Signaling ◽  
Progression Of Kidney Disease ◽  
Central Member

The Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway is a multifaceted transduction system that regulates cellular responses to incoming signaling ligands. STAT3 is a central member of the JAK/STAT signaling cascade and has long been recognized for its increased transcriptional activity in cancers and autoimmune disorders but has only recently been in the spotlight for its role in the progression of kidney disease. Although genetic knockout and manipulation studies have demonstrated the salutary benefits of inhibiting STAT3 activity in several kidney disease models, pharmacological inhibition has yet to make it to the clinical forefront. In recent years, significant effort has been aimed at suppressing STAT3 activation for treatment of cancers, which has led to the development of a wide variety of STAT3 inhibitors, but only a handful have been tested in kidney disease models. Here, we review the detrimental role of dysregulated STAT3 activation in a variety of kidney diseases and the current progress in the treatment of kidney diseases with pharmacological inhibition of STAT3 activity.

scholarly journals A Personalized Glomerulus Chip Engineered from Stem Cell-Derived Epithelium and Vascular Endothelium

Micromachines ◽  
2021 ◽  
Vol 12 (8) ◽  
pp. 967
Author(s):  
Yasmin Roye ◽  
Rohan Bhattacharya ◽  
Xingrui Mou ◽  
Yuhao Zhou ◽  
Morgan A. Burt ◽  
...  
Keyword(s):  
Stem Cell ◽  
Kidney Disease ◽  
Structural Integrity ◽  
Disease Modeling ◽  
Patient Specific ◽  
Ips Cell ◽  
Filtration Barrier ◽  
Disease Mechanisms ◽  
Kidney Glomerulus

Progress in understanding kidney disease mechanisms and the development of targeted therapeutics have been limited by the lack of functional in vitro models that can closely recapitulate human physiological responses. Organ Chip (or organ-on-a-chip) microfluidic devices provide unique opportunities to overcome some of these challenges given their ability to model the structure and function of tissues and organs in vitro. Previously established organ chip models typically consist of heterogenous cell populations sourced from multiple donors, limiting their applications in patient-specific disease modeling and personalized medicine. In this study, we engineered a personalized glomerulus chip system reconstituted from human induced pluripotent stem (iPS) cell-derived vascular endothelial cells (ECs) and podocytes from a single patient. Our stem cell-derived kidney glomerulus chip successfully mimics the structure and some essential functions of the glomerular filtration barrier. We further modeled glomerular injury in our tissue chips by administering a clinically relevant dose of the chemotherapy drug Adriamycin. The drug disrupts the structural integrity of the endothelium and the podocyte tissue layers, leading to significant albuminuria as observed in patients with glomerulopathies. We anticipate that the personalized glomerulus chip model established in this report could help advance future studies of kidney disease mechanisms and the discovery of personalized therapies. Given the remarkable ability of human iPS cells to differentiate into almost any cell type, this work also provides a blueprint for the establishment of more personalized organ chip and ‘body-on-a-chip’ models in the future.

scholarly journals Integration of genetic and histopathology data in interpretation of kidney disease

2020 ◽  
Vol 35 (7) ◽  
pp. 1113-1132
Author(s):  
Susan L Murray ◽  
Neil K Fennelly ◽  
Brendan Doyle ◽  
Sally Ann Lynch ◽  
Peter J Conlon
Keyword(s):  
Kidney Disease ◽  
Renal Biopsy ◽  
Kidney Diseases ◽  
Genomic Medicine ◽  
Disease Diagnosis ◽  
Diagnostic Information ◽  
Significant Burden ◽  
Diagnostic Modalities ◽  
Enhance Patient Care ◽  
Inherited Kidney Disease

Abstract For many years renal biopsy has been the gold standard for diagnosis in many forms of kidney disease. It provides rapid, accurate and clinically useful information in most individuals with kidney disease. However, in recent years, other diagnostic modalities have become available that may provide more detailed and specific diagnostic information in addition to, or instead of, renal biopsy. Genomics is one of these modalities. Previously prohibitively expensive and time consuming, it is now increasingly available and practical in a clinical setting for the diagnosis of inherited kidney disease. Inherited kidney disease is a significant cause of kidney disease, in both the adult and paediatric populations. While individual inherited kidney diseases are rare, together they represent a significant burden of disease. Because of the heterogenicity of inherited kidney disease, diagnosis and management can be a challenge and often multiple diagnostic modalities are needed to arrive at a diagnosis. We present updates in genomic medicine for renal disease, how genetic testing integrates with our knowledge of renal histopathology and how the two modalities may interact to enhance patient care.

scholarly journals Evaluation of endogenous miRNA reference genes across different zebrafish strains, developmental stages and kidney disease models

2021 ◽  
Author(s):  
Florian Siegerist ◽  
Tim Lange ◽  
Anna Iervolino ◽  
Thor Magnus Koppe ◽  
Weibin Zhou ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Reference Genes ◽  
Developmental Stages ◽  
Kidney Diseases ◽  
Morphological Changes ◽  
Group Differences ◽  
Disease Models ◽  
Endogenous Reference ◽  
Process Architecture

The majority of kidney diseases arise from the loss of podocytes and from morphological changes of their highly complex foot process architecture, which inevitably leads to a reduced kidney filtration and total loss of kidney function. It could have been shown that microRNAs (miRs) play a pivotal role in the pathogenesis of podocyte-associated kidney diseases. Due to their fully functioning pronephric kidney, larval zebrafish have become a popular vertebrate model, to study kidney diseases in vivo. Unfortunately, there is no consensus about a proper normalization strategy of RT-qPCR based miRNA expression data in zebrafish. In this study we analyzed 9 preselected candidates dre-miR-92a-3p, dre-miR-206-3p, dre-miR-99-1, dre-miR-92b-3p, dre-miR-363-3p, dre-let-7e, dre-miR-454a, dre-miR-30c-5p, dre-miR-126a-5p for their capability as endogenous reference genes in zebrafish experiments. Expression levels of potential candidates were measured in 3 different zebrafish strains, different developmental stages and in different kidney disease models by RT-qPCR. Expression values were analyzed with NormFinder, BestKeeper, GeNorm, and DeltaCt and were tested for inter-group differences. All candidates show an abundant expression throughout all samples and relatively high stability. The most stable candidate without significant inter-group differences was dre-miR-92b-3p making it a suitable endogenous reference gene for RT-qPCR-based miR expression zebrafish studies. The majority of kidney diseases arise from the loss of podocytes and from morphological changes of their highly complex foot process architecture, which inevitably leads to a reduced kidney filtration and total loss of kidney function. It could have been shown that microRNAs (miRs) play a pivotal role in the pathogenesis of podocyte-associated kidney diseases. Due to their fully functioning pronephric kidney, larval zebrafish have become a popular vertebrate model, to study kidney diseases in vivo. Unfortunately, there is no consensus about a proper normalization strategy of RT-qPCR-based miRNA expression data in zebrafish. In this study we analyzed 9 preselected candidates dre-miR-92a-3p, dre-miR-206-3p, dre-miR-99-1, dre-miR-92b-3p, dre-miR-363-3p, dre-let-7e, dre-miR-454a, dre-miR-30c-5p, dre-miR-126a-5p for their capability as endogenous reference genes in zebrafish experiments. Expression levels of potential candidates were measured in 3 different zebrafish strains, different developmental stages, and in different kidney disease models by RT-qPCR. Expression values were analyzed with NormFinder, BestKeeper, GeNorm, and DeltaCt and were tested for inter-group differences. All candidates show an abundant expression throughout all samples and relatively high stability. The most stable candidate without significant inter-group differences was dre-miR-92b-3p making it a suitable endogenous reference gene for RT-qPCR-based miR expression zebrafish studies.

Stroke in chronic renal failure

2008 ◽  
Vol 149 (15) ◽  
pp. 691-696
Author(s):  
Dániel Bereczki
Keyword(s):  
Risk Factors ◽  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Renal Disease ◽  
Chronic Renal Disease ◽  
Kidney Diseases ◽  
Cerebrovascular Diseases ◽  
Lipid Lowering ◽  
Increased Risk ◽  
Intracerebral Hemorrhages

Chronic kidney diseases and cardiovascular diseases have several common risk factors like hypertension and diabetes. In chronic renal disease stroke risk is several times higher than in the average population. The combination of classical risk factors and those characteristic of chronic kidney disease might explain this increased risk. Among acute cerebrovascular diseases intracerebral hemorrhages are more frequent than in those with normal kidney function. The outcome of stroke is worse in chronic kidney disease. The treatment of stroke (thrombolysis, antiplatelet and anticoagulant treatment, statins, etc.) is an area of clinical research in this patient group. There are no reliable data on the application of thrombolysis in acute stroke in patients with chronic renal disease. Aspirin might be administered. Carefulness, individual considerations and lower doses might be appropriate when using other treatments. The condition of the kidney as well as other associated diseases should be considered during administration of antihypertensive and lipid lowering medications.

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