scholarly journals Characterisation of transcription factor profiles in polycystic kidney disease (PKD): identification and validation of STAT3 and RUNX1 in the injury/repair response and PKD progression

2019 ◽  
Vol 97 (12) ◽  
pp. 1643-1656 ◽  
Author(s):  
Chiara Formica ◽  
Tareq Malas ◽  
Judit Balog ◽  
Lotte Verburg ◽  
Peter A. C. ‘t Hoen ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Kidney Disease ◽  
Polycystic Kidney Disease ◽  
Molecular Mechanisms ◽  
Expression Profiles ◽  
Meta Analysis ◽  
List Type ◽  
Polycystic Kidney ◽  
Altered Expression ◽  
Injury Repair

Abstract Autosomal dominant polycystic kidney disease (ADPKD) is the most common genetic renal disease, caused in the majority of the cases by a mutation in either the PKD1 or the PKD2 gene. ADPKD is characterised by a progressive increase in the number and size of cysts, together with fibrosis and distortion of the renal architecture, over the years. This is accompanied by alterations in a complex network of signalling pathways. However, the underlying molecular mechanisms are not well characterised. Previously, we defined the PKD Signature, a set of genes typically dysregulated in PKD across different disease models from a meta-analysis of expression profiles. Given the importance of transcription factors (TFs) in modulating disease, we focused in this paper on characterising TFs from the PKD Signature. Our results revealed that out of the 1515 genes in the PKD Signature, 92 were TFs with altered expression in PKD, and 32 of those were also implicated in tissue injury/repair mechanisms. Validating the dysregulation of these TFs by qPCR in independent PKD and injury models largely confirmed these findings. STAT3 and RUNX1 displayed the strongest activation in cystic kidneys, as demonstrated by chromatin immunoprecipitation (ChIP) followed by qPCR. Using immunohistochemistry, we showed a dramatic increase of expression after renal injury in mice and cystic renal tissue of mice and humans. Our results suggest a role for STAT3 and RUNX1 and their downstream targets in the aetiology of ADPKD and indicate that the meta-analysis approach is a viable strategy for new target discovery in PKD. Key messages We identified a list of transcription factors (TFs) commonly dysregulated in ADPKD. Out of the 92 TFs identified in the PKD Signature, 35% are also involved in injury/repair processes. STAT3 and RUNX1 are the most significantly dysregulated TFs after injury and during PKD progression. STAT3 and RUNX1 activity is increased in cystic compared to non-cystic mouse kidneys. Increased expression of STAT3 and RUNX1 is observed in the nuclei of renal epithelial cells, also in human ADPKD samples.

scholarly journals Meta-analysis of polycystic kidney disease expression profiles defines strong involvement of injury repair processes

2017 ◽  
Vol 312 (4) ◽  
pp. F806-F817 ◽  
Author(s):  
Tareq B. Malas ◽  
Chiara Formica ◽  
Wouter N. Leonhard ◽  
Pooja Rao ◽  
Zoraide Granchi ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Mouse Model ◽  
Polycystic Kidney Disease ◽  
Mutant Mouse ◽  
Expression Profiles ◽  
Meta Analysis ◽  
Polycystic Kidney ◽  
Mesenchymal Transition ◽  
Injury Repair ◽  
Signature Genes

Polycystic kidney disease (PKD) is a major cause of end-stage renal disease. The disease mechanisms are not well understood and the pathogenesis toward renal failure remains elusive. In this study, we present the first RNASeq analysis of a Pkd1-mutant mouse model in a combined meta-analysis with other published PKD expression profiles. We introduce the PKD Signature, a set of 1,515 genes that are commonly dysregulated in PKD studies. We show that the signature genes include many known and novel PKD-related genes and functions. Moreover, genes with a role in injury repair, as evidenced by expression data and/or automated literature analysis, were significantly enriched in the PKD Signature, with 35% of the PKD Signature genes being directly implicated in injury repair. NF-κB signaling, epithelial-mesenchymal transition, inflammatory response, hypoxia, and metabolism were among the most prominent injury or repair-related biological processes with a role in the PKD etiology. Novel PKD genes with a role in PKD and in injury were confirmed in another Pkd1-mutant mouse model as well as in animals treated with a nephrotoxic agent. We propose that compounds that can modulate the injury-repair response could be valuable drug candidates for PKD treatment.

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 Establishment of a Ciliogenesis-Associated Signaling Model for Polycystic Kidney Disease

2021 ◽  
pp. 1-9
Author(s):  
Ling Lu ◽  
Qiuling Liu ◽  
Lei Zhi ◽  
Xuchun Che ◽  
Bo Xiao ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Polycystic Kidney Disease ◽  
Molecular Mechanisms ◽  
Differential Expression Analysis ◽  
Valuable Insight ◽  
Polycystic Kidney ◽  
Hub Genes ◽  
Zebrafish Model

<b><i>Background:</i></b> Polycystic kidney disease (PKD) represents the most prevalent inherited progressive kidney disorder in humans. Due to complexity of the genetic network behind the disease, the molecular mechanisms of PKD are still poorly understood yet. <b><i>Objectives:</i></b> This study aimed to develop a ciliogenesis-associated gene network for PKD patients and comprehensively understand the molecular mechanisms underlying the disease. <b><i>Method:</i></b> The potential hub genes were selected based on the differential expression analysis from the GEO database. Meanwhile, the primary hub genes were further elucidated by both in vivo and in vitro experiments. <b><i>Results:</i></b> In this study, we established a comprehensive differentially expressed genes profile (including <i>GNAS, PI4KB, UMOD, SLC7A13,</i> and <i>MIOX</i>) for PKD patients compared with the control specimen. At the same time, enrichment analysis was utilized to demonstrate that the G-protein-related signaling and cilia assembling signaling pathways were closely associated with PKD development. The further investigations of the interaction between 2 genes (<i>GNAS</i> and <i>PI4KB</i>) with in vivo and in vitro analyses revealed that PI4KB functioned as a downstream factor for GNAS and spontaneously activated the phosphorylation of Akt into p-Akt for ciliogenesis in PKD formation. The <i>PI4KB</i> depletion mutant zebrafish model displayed a PKD phenotype as well as absence of primary cilia in the kidney<i>.</i> <b><i>Conclusions:</i></b> Collectively, our work discovered an innovative potential signaling pathway model for PKD formation, which provided a valuable insight for future study of the mechanism of this disease.

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.

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