scholarly journals Metabolic Changes in Polycystic Kidney Disease as a Potential Target for Systemic Treatment

2020 ◽  
Vol 21 (17) ◽  
pp. 6093
Author(s):  
Sophie Haumann ◽  
Roman-Ulrich Müller ◽  
Max C. Liebau
Keyword(s):  
Kidney Disease ◽  
Polycystic Kidney Disease ◽  
Autosomal Recessive ◽  
Molecular Mechanisms ◽  
Autosomal Dominant ◽  
Systemic Treatment ◽  
Metabolic Changes ◽  
Polycystic Kidney ◽  
Potential Target ◽  
Autosomal Dominant Polycystic Kidney

Autosomal recessive and autosomal dominant polycystic kidney disease (ARPKD, ADPKD) are systemic disorders with pronounced hepatorenal phenotypes. While the main underlying genetic causes of both ARPKD and ADPKD have been well-known for years, the exact molecular mechanisms resulting in the observed clinical phenotypes in the different organs, remain incompletely understood. Recent research has identified cellular metabolic changes in PKD. These findings are of major relevance as there may be an immediate translation into clinical trials and potentially clinical practice. Here, we review important results in the field regarding metabolic changes in PKD and their modulation as a potential target of systemic treatment.

Mutation variability at polycystic kidney disease detected by NGS

2020 ◽  
pp. 25-37
Author(s):  
Н.Н. Вассерман ◽  
А.В. Поляков
Keyword(s):  
Kidney Disease ◽  
Polycystic Kidney Disease ◽  
Autosomal Recessive ◽  
Target Genes ◽  
Autosomal Dominant ◽  
Molecular Genetic Analysis ◽  
Polycystic Kidney ◽  
Parallel Sequencing ◽  
Pkd1 Gene ◽  
Autosomal Dominant Polycystic Kidney

Поликистозная болезнь почек (ПП) является клинически и генетически гетерогенной группой заболеваний, может наследоваться как аутосомно-доминантно (АД), так и аутосомно-рецессивно (АР). К развитию АР ПП приводят мутации в гене PKHD1. Большинство мутаций при АД ПП находят в гене PKD1 (80-85%). Примерно в 15% случаев мутации выявляют в гене PKD2. Клиническое и генетическое разнообразие ПП требует поиска мутаций в нескольких генах, поэтому он является трудоемким, дорогостоящим и требует много времени. Метод массового параллельного секвенирования (МПС) позволяет проводить поиск мутаций в нескольких генах одновременно независимо от их размера. Проведен поиск мутаций в 254 семьях с ПП методом МПС с использованием панели, включающей гены PKHD1, PKD1, PKD2, HNF1B и GANAB. Два варианта в гене PKHD1 было идентифицировано в 49 семьях (19%), один вариант найден в 9 случаях (3,5%); в гене PKD1 обнаружено 62 варианта (24,5%), в гене PKD2 - 6 вариантов (2,5%), в гене HNF1B - 9 вариантов (3,5%). В 119 семьях, что составило 47%, мутации найдены не были. У больных из семей с генеалогически установленным АД типом наследования в большинстве случаев (39 из 66; 59%) выявлены варианты в гене PKD1, приводящие к ПП. Из 59 изолированных случаев ПП в 17% (10 человек) идентифицированы 2 варианта в гене PНKD1, в 20% (12 человек) - в гене PKD1. При неизвестном типе наследования (129 случаев) в 29,5% (38 чел.) найдены 2 варианта в гене PНKD1, в 8,5% (11 чел.) - в гене PKD1, в 3% (4 чел.) - в гене PKD2, в 4% (5 чел.) - в гене HNF1B. Таким образом, МПС относительно быстро позволяет проводить молекулярно-генетический анализ одновременно в нескольких генах у больных с признаками ПП. Polycystic kidney disease is a heterogeneous group of autosomal dominant or autosomal recessive disorders with age of manifestation varying from prenatal period to adulthood. Autosomal recessive polycystic kidney disease is caused by mutations in the PKHD1 gene. Approximately 85% of all autosomal dominant polycystic kidney disease cases are caused by mutations in the PKD1 gene, and around 15% - by mutations in the PKD2 gene. All these genes are large, and mutations were found to be scattered throughout the genes without any clustering. Therefore, mutation detection requires a lot of time, money, and effort. Due to clinical and genetic diversity of polycystic kidney disease, the search for mutations has to be carried out in several genes. Mass parallel sequencing (MPS) allows to analyze several genes simultaneously regardless of their size. 254 families with polycystic kidney disease were examined using mass parallel sequencing with a gene panel that included PKHD1, PKD1, PKD2, HNF1B and GANAB. Two variants in PKHD1 were found in 49 families (19%), one variant - in 9 families (3.5%); in PKD1 62 variants were detected (24.5%), in PKD2 - 6 variants (2.5%), in HNF1B - 9 variants (3.5%). In 119 families (47%) there were no mutations in the target genes. Among 66 patients from families with autosomal dominant polycystic kidney disease, 39 patients (59%) had mutations in the PKD1 gene. Out of 59 sporadic cases, 10 patients (17%) had 2 variants in PНKD1, 12 patients (20%) - in PKD1. 38 patients (29.5%) out of 129 patients with unknown type of inheritance had 2 variants in PНKD1, 11 patients (8.5%) - in PKD1, 4 patients (3%) - in PKD2, 5 patients (4%) - in HNF1B. Mass parallel sequencing allows to carry out relatively rapid molecular genetic analysis of several genes simultaneously for patients with symptoms of polycystic kidney disease.

Activation of NRF2 ameliorates oxidative stress and cystogenesis in autosomal dominant polycystic kidney disease

2020 ◽  
Vol 12 (554) ◽  
pp. eaba3613 ◽  
Author(s):  
Yi Lu ◽  
Yongzhan Sun ◽  
Zhiheng Liu ◽  
Yumei Lu ◽  
Xu Zhu ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Kidney Disease ◽  
Polycystic Kidney Disease ◽  
Molecular Mechanisms ◽  
Autosomal Dominant ◽  
Redox Homeostasis ◽  
Separation Mechanism ◽  
Related Factor ◽  
Polycystic Kidney ◽  
Autosomal Dominant Polycystic Kidney

Oxidative stress is emerging as a crucial contributor to the pathogenesis of autosomal dominant polycystic kidney disease (ADPKD), but the molecular mechanisms underlying the disturbed redox homeostasis in cystic cells remain elusive. Here, we identified the impaired activity of the NRF2 (nuclear factor erythroid 2–related factor 2) antioxidant pathway as a driver of oxidative damage and ADPKD progression. Using a quantitative proteomic approach, together with biochemical analyses, we found that increased degradation of NRF2 protein suppressed the NRF2 antioxidant pathway in ADPKD mouse kidneys. In a cohort of patients with ADPKD, reactive oxygen species (ROS) frequently accumulated, and their production correlated negatively with NRF2 abundance and positively with disease severity. In an orthologous ADPKD mouse model, genetic deletion of Nrf2 further increased ROS generation and promoted cyst growth, whereas pharmacological induction of NRF2 reduced ROS production and slowed cystogenesis and disease progression. Mechanistically, pharmacological induction of NRF2 remodeled enhancer landscapes and activated NRF2-bound enhancer-associated genes in ADPKD cells. The activation domain of NRF2 formed phase-separated condensates with MEDIATOR complex subunit MED16 in vitro, and optimal Mediator recruitment to genomic loci depended on NRF2 in vivo. Together, these findings indicate that NRF2 remodels enhancer landscapes and activates its target genes through a phase separation mechanism and that activation of NRF2 represents a promising strategy for restoring redox homeostasis and combatting ADPKD.

scholarly journals Insights into cellular and molecular basis for urinary tract infection in autosomal-dominant polycystic kidney disease

2017 ◽  
Vol 313 (5) ◽  
pp. F1077-F1083 ◽  
Author(s):  
Chao Gao ◽  
Long Zhang ◽  
Ye Zhang ◽  
Darren P. Wallace ◽  
Reynold I. Lopez-Soler ◽  
...  
Keyword(s):  
Urinary Tract Infection ◽  
Urinary Tract ◽  
Kidney Disease ◽  
Tract Infection ◽  
Polycystic Kidney Disease ◽  
Molecular Mechanisms ◽  
Autosomal Dominant ◽  
Immune Defense ◽  
Polycystic Kidney ◽  
Autosomal Dominant Polycystic Kidney

Urinary tract infection (UTI) is a broad term referring to an infection of the kidneys, ureters, bladder, and/or urethra. Because of its prevalence, frequent recurrence, and rising resistance to antibiotics, UTI has become a challenge in clinical practice. Autosomal-dominant polycystic kidney disease (ADPKD) is the most common monogenic disorder of the kidney and is characterized by the growth of fluid-filled cysts in both kidneys. Progressive cystic enlargement, inflammation, and interstitial fibrosis result in nephron loss with subsequent decline in kidney function. ADPKD patients frequently develop UTI; however, the cellular and molecular mechanisms responsible for the high UTI incidence in ADPKD patients remain virtually unaddressed. Emerging evidence suggests that α-intercalated cells (α-ICs) of the collecting ducts function in the innate immune defense against UTI. α-ICs inhibit bacterial growth by acidifying urine and secreting neutrophil gelatinase-associated lipocalin (NGAL) that chelates siderophore-containing iron. It is necessary to determine, therefore, if ADPKD patients with recurrent UTI have a reduced number and/or impaired function of α-ICs. Identification of the underlying cellular and molecular mechanisms may lead to the development of novel strategies to reduce UTI in ADPKD.

scholarly journals Treatment of autosomal recessive and autosomal dominant polycystic kidney disease

2019 ◽  
Vol 64 (2) ◽  
pp. 22-29
Author(s):  
E. F. Andreeva ◽  
N. D. Savenkova
Keyword(s):  
Kidney Disease ◽  
Polycystic Kidney Disease ◽  
Autosomal Recessive ◽  
Autosomal Dominant ◽  
Kinase Inhibitor ◽  
Mtor Inhibitors ◽  
Somatostatin Analogues ◽  
Polycystic Kidney ◽  
V2 Receptor ◽  
Autosomal Dominant Polycystic Kidney

The article reflects the genetic variants of polycystic kidney disease, describes the modern strategy for the treatment of polycystic kidney disease in children and adults. The authors present the results of clinical trials of vasopressin V2 receptor antagonists (tolvaptan, liksivaptan), a multi-kinase inhibitor (tezevatinib), somatostatin analogues (lankreotide, octreotide), statins (pravastatin), mTOR inhibitors (everolimus, sirolimus), metformin in patients with autosomal recessive and autosomal polycystic kidney disease. The authors discuss the factors determining the prognosis and outcome of these diseases.

MO007ANALYSIS OF CALCIUM SIGNALING IN AUTOSOMAL DOMINANT POLYCYSTIC KIDNEY DISEASE (ADPKD)

2021 ◽  
Vol 36 (Supplement_1) ◽  
Author(s):  
Dorien Van Giel ◽  
Jean-Paul Decuypere ◽  
Djalila Mekahli ◽  
Rudi Vennekens
Keyword(s):  
Kidney Disease ◽  
Epithelial Cells ◽  
Polycystic Kidney Disease ◽  
Molecular Mechanisms ◽  
Autosomal Dominant ◽  
Trp Channels ◽  
Cell Model ◽  
Healthy Controls ◽  
Polycystic Kidney ◽  
Autosomal Dominant Polycystic Kidney

Abstract Background and Aims Autosomal Dominant Polycystic Kidney Disease (ADPKD) is an inheritable kidney disease characterized by the development of fluid-filled cysts in all nephron segments, leading to loss of renal function. Mutations in PKD1 or PKD2, which encode polycystin-1 and polycystin-2, are the most common cause of ADPKD. The molecular mechanisms underlying cystogenesis are poorly characterized but it is postulated that disturbed calcium homeostasis is a primary event in cystogenesis. The precise molecular players that cause this disturbance are still a poorly explored area, especially in relevant human cell types. We therefore aim to characterize the profile of calcium-coupled receptors and channels in a human renal epithelial cell model, to identify which receptors and channels are present and whether their function is affected in ADPKD. Method Human urine-derived conditionally immortalized proximal tubule epithelial cells (ciPTECs) of ADPKD patients and healthy controls were screened for calcium-coupled GPCRs, using a GPCR agonist library on Fura-2 loaded cell populations seeded in 96-well format using the Flexstation3 (Molecular Devices). Validation of specific hits was done using single-cell measurements with a fluorescence microscope and built-in perfusion system. The expression of TRP channels and STIM/Orai proteins was determined via qPCR. Results From a library of 418 GPCR agonists a selective amount of calcium-coupled GPCRs was found functionally active in ciPTECs. ciPTECs from both healthy controls and ADPKD patients were found to functionally express purinergic -, histamine -, serotonin and dopamine receptors. Through qPCR we found expression of various TRP channels, including TRPML1, TRPC1/3, TRPM3/4/7, TRPV4 and TRPA1, as well as high expression of STIM1/2 and Orai1/2/3. Conclusion We describe the first thorough characterization of molecular players involved in calcium signalling mechanisms in human renal epithelial cells, including the profile of calcium-coupled GPCRs and the expression of TRP channels and STIM/Orai proteins, of further interest to investigate disturbed calcium dynamics in ADPKD.

scholarly journals AUTOSOMAL RECESSIVE POLYCYSTIC KIDNEY DISEASE IN THE STRUCTURE OF CYSTIC DYSPLASIA IN CHILDREN

2018 ◽  
Vol 63 (5) ◽  
pp. 172-176 ◽  
Author(s):  
T. P. Makarova ◽  
V. P. Bulatov ◽  
N. V. Samoylova ◽  
G. M. Samoylova ◽  
L. V. Poladova ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Polycystic Kidney Disease ◽  
Autosomal Recessive ◽  
Autosomal Dominant ◽  
Clinical Laboratory ◽  
Renal Dysplasia ◽  
Polycystic Kidney ◽  
Cystic Renal Dysplasia ◽  
Congenital Kidney Anomalies ◽  
Autosomal Dominant Polycystic Kidney

Cystic dysplasia is a heterogeneous group of diseases, with 12–15% share in the structure of congenital kidney anomalies and 8–10% share in the structure of the causes of chronic renal failure in children. The article presents the results of observation of patients with polycystic kidney disease. To study the clinical features of the course of various forms of cystic dysplasia in children we analyzed the histories of children with autosomal recessive and autosomal dominant polycystic kidney disease. We revealed clinical, laboratory and instrumental features of the course of various types of cystic renal dysplasia.

scholarly journals Somatic Mutations in Renal Cyst Epithelium in Autosomal Dominant Polycystic Kidney Disease

2018 ◽  
Vol 29 (8) ◽  
pp. 2139-2156 ◽  
Author(s):  
Adrian Y. Tan ◽  
Tuo Zhang ◽  
Alber Michaeel ◽  
Jon Blumenfeld ◽  
Genyan Liu ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Polycystic Kidney Disease ◽  
Long Range ◽  
Molecular Mechanisms ◽  
Somatic Mutations ◽  
Autosomal Dominant ◽  
Sequencing Data ◽  
Polycystic Kidney ◽  
Long Range Pcr ◽  
Autosomal Dominant Polycystic Kidney

BackgroundAutosomal dominant polycystic kidney disease (ADPKD) is a ciliopathy caused by mutations in PKD1 and PKD2 that is characterized by renal tubular epithelial cell proliferation and progressive CKD. Although the molecular mechanisms involved in cystogenesis are not established, concurrent inactivating constitutional and somatic mutations in ADPKD genes in cyst epithelium have been proposed as a cellular recessive mechanism.MethodsWe characterized, by whole-exome sequencing (WES) and long-range PCR techniques, the somatic mutations in PKD1 and PKD2 genes in renal epithelial cells from 83 kidney cysts obtained from nine patients with ADPKD, for whom a constitutional mutation in PKD1 or PKD2 was identified.ResultsComplete sequencing data by long-range PCR and WES was available for 63 and 65 cysts, respectively. Private somatic mutations of PKD1 or PKD2 were identified in all patients and in 90% of the cysts analyzed; 90% of these mutations were truncating, splice site, or in-frame variations predicted to be pathogenic mutations. No trans-heterozygous mutations of PKD1 or PKD2 genes were identified. Copy number changes of PKD1 ranging from 151 bp to 28 kb were observed in 12% of the cysts. WES also identified significant mutations in 53 non-PKD1/2 genes, including other ciliopathy genes and cancer-related genes.ConclusionsThese findings support a cellular recessive mechanism for cyst formation in ADPKD caused primarily by inactivating constitutional and somatic mutations of PKD1 or PKD2 in kidney cyst epithelium. The potential interactions of these genes with other ciliopathy- and cancer-related genes to influence ADPKD severity merits further evaluation.

scholarly journals Extracranial Aneurysms in 2 Patients with Autosomal Recessive Polycystic Kidney Disease

2017 ◽  
Vol 7 (2) ◽  
pp. 34-42 ◽  
Author(s):  
Daniel S. Elchediak ◽  
Anne Marie Cahill ◽  
Emma E. Furth ◽  
Bernard S. Kaplan ◽  
Erum A. Hartung
Keyword(s):  
Kidney Disease ◽  
Polycystic Kidney Disease ◽  
Autosomal Recessive ◽  
Molecular Mechanisms ◽  
Vascular Malformations ◽  
Gastric Artery ◽  
Polycystic Kidney ◽  
Vascular Integrity ◽  
Vascular Abnormalities ◽  
Autosomal Dominant Polycystic Kidney

Unlike autosomal dominant polycystic kidney disease (ADPKD), autosomal recessive polycystic kidney disease (ARPKD) is not generally known to be associated with vascular abnormalities. Only 4 cases of ARPKD patients with intracranial aneurysms have been reported previously. We present 2 ARPKD patients with extracranial vascular abnormalities: a young man with infrarenal aortic and iliac artery aneurysms complicated by dissection and a teenage girl with multiple splenic and gastric artery aneurysms and arterial vascular malformations. These cases raise the question of whether vascular integrity and development may be impaired in ARPKD, perhaps through molecular mechanisms overlapping with ADPKD. This possibility is supported by studies in mice that show ARPKD gene expression in the walls of large blood vessels.

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