SMYD3 Controls Ciliogenesis by Regulating Distinct Centrosomal Proteins and Intraflagellar Transport Trafficking.

The primary cilium is a microtubule-based sensory organelle that plays a critical role in signaling pathways and cell cycle progression. Defects in the structure and/or function of the primary cilium result in developmental diseases collectively known as ciliopathies. However, the constituents and regulatory mechanisms of the primary cilium are not fully understood.

DNA methyltransferase 1 (DNMT1) promotes cyst growth and epigenetic age acceleration in autosomal dominant polycystic kidney disease.

Alteration of DNA methylation leads to diverse diseases, and the dynamic changes of DNA methylation (DNAm) on sets of CpG dinucleotides in mammalian genomes are termed "DNAm age" and "epigenetic clocks" that can predict chronological age. However, whether and how dysregulation of DNA methylation promotes cyst progression and epigenetic age acceleration in autosomal dominant polycystic kidney disease (ADPKD) remains elusive. Here, we show that DNA methyltransferase 1 (DNMT1) is upregulated in cystic kidney epithelial cells and tissues and that knockout of Dnmt1 and targeting DNMT1 with hydralazine, a safe demethylating agent, delays cyst growth in Pkd1 mutant kidneys and extends life span of Pkd1 conditional knockout mice.

Overexpression of SMYD3 Promotes Autosomal Dominant Polycystic Kidney Disease by Mediating Cell Proliferation and Genome Instability.

Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited kidney disorder worldwide and progresses to end-stage renal disease (ESRD). However, its precise mechanism is not fully understood. In recent years, epigenetic reprogramming has drawn increasing attention regarding its effect on cyst growth.

Polycystin-1 Interacting Protein-1 (CU062) Interacts with the Ectodomain of Polycystin-1 (PC1).

The gene, encoding protein polycystin-1 (PC1), is responsible for 85% of cases of autosomal dominant polycystic kidney disease (ADPKD). PC1 has been shown to be present in urinary exosome-like vesicles (PKD-ELVs) and lowered in individuals with germline mutations. A label-free mass spectrometry comparison of urinary PKD-ELVs from normal individuals and those with mutations showed that several proteins were reduced to a degree that matched the decrease observed in PC1 levels.

Single-Cell and CellChat Resolution Identifies Collecting Duct Cell Subsets and Their Communications with Adjacent Cells in PKD Kidneys.

ADPKD is a genetic disorder with a molecular complexity that remains poorly understood. In this study, we sampled renal cells to construct a comprehensive and spatiotemporally resolved gene expression atlas in whole mutant polycystic mouse kidneys at single-cell resolution. We characterized cell diversity and identified novel collecting duct (CD) cell subtypes in cystic kidneys.

The GPCR properties of polycystin-1- A new paradigm.

Polycystin-1 (PC1) is an 11-transmembrane (TM) domain-containing protein encoded by the gene, the most frequently mutated gene leading to autosomal dominant polycystic kidney disease (ADPKD). This large (> 462 kDal) protein has a complex posttranslational maturation process, with over five proteolytic cleavages having been described, and is found at multiple cellular locations. The initial description of the binding and activation of heterotrimeric Gαi/o by the juxtamembrane region of the PC1 cytosolic C-terminal tail (C-tail) more than 20 years ago opened the door to investigations, and controversies, into PC1's potential function as a novel G protein-coupled receptor (GPCR).

Transcription factor FoxM1 promotes cyst growth in PKD1 mutant ADPKD.

Autosomal dominant polycystic kidney disease (ADPKD) is driven by mutations in the PKD1 and PKD2 genes, and it is characterized by renal cyst formation, inflammation and fibrosis. Forkhead box protein M1 (FoxM1), a transcription factor of the Forkhead box (Fox) protein super family, has been reported to promote tumor formation, inflammation and fibrosis in many organs. However, the role and mechanism of FoxM1 in regulation of ADPKD progression is still poorly understood.

The lonidamine derivative H2-gamendazole reduces cyst formation in polycystic kidney disease.

Autosomal dominant polycystic kidney disease (ADPKD) is a debilitating renal neoplastic disorder with limited treatment options. It is characterized by the formation of large fluid-filled cysts that develop from kidney tubules through abnormal cell proliferation and cyst-filling fluid secretion driven by cAMP-dependent Cl secretion. We tested the effectiveness of the indazole carboxylic acid H2-gamendazole (H2-GMZ), a derivative of lonidamine, to inhibit these processes using in vitro and in vivo models of ADPKD.

Vasopressin Receptor Type-2 Mediated Signaling in Renal Cell Carcinoma Stimulates Stromal Fibroblast Activation.

Vasopressin type-2 receptor (V2R) is ectopically expressed and plays a pathogenic role in clear cell renal cell carcinoma (ccRCC) tumor cells. Here we examined how V2R signaling within human ccRCC tumor cells (Caki1 cells) stimulates stromal cancer-associated fibroblasts (CAFs). We found that cell culture conditioned media from Caki1 cells increased activation, migration, and proliferation of fibroblasts in vitro, which was inhibited by V2R gene silencing in Caki1 cells.

Ttc21b deficiency attenuates autosomal dominant polycystic kidney disease in a kidney tubular- and maturation-dependent manner.

Primary cilia are sensory organelles built and maintained by intraflagellar transport (IFT) multiprotein complexes. Deletion of several IFT-B genes attenuates polycystic kidney disease (PKD) severity in juvenile and adult autosomal dominant polycystic kidney disease (ADPKD) mouse models. However, deletion of an IFT-A adaptor, Tulp3, attenuates PKD severity in adult mice only.

Antioxidant enzyme peroxiredoxin 5 regulates cyst growth and ciliogenesis via modulating Plk1 stability.

Oxidative stress is emerging as a contributing factor to the homeostasis in cystic diseases. However, the role antioxidant enzymes play in the pathogenesis of autosomal dominant polycystic kidney disease (ADPKD) remains elusive. Peroxiredoxin 5 (Prdx5) is an antioxidant enzyme that catalyzes the reduction of H O and alkyl hydroperoxide and plays an important role in different biological processes.

The tyrosine-kinase inhibitor Nintedanib ameliorates autosomal-dominant polycystic kidney disease.

Autosomal-dominant polycystic kidney disease (ADPKD) is the most common inherited kidney disease and is characterized by progressive growth of fluid-filled cysts. Growth factors binding to receptor tyrosine kinases (RTKs) stimulate cell proliferation and cyst growth in PKD. Nintedanib, a triple RTK inhibitor, targets the vascular endothelial growth-factor receptor (VEGFR), platelet-derived growth-factor receptor (PDGFR), and fibroblast growth-factor receptor (FGFR), and is an approved drug for the treatment of non-small-cell lung carcinoma and idiopathic lung fibrosis.

Quinomycin A reduces cyst progression in polycystic kidney disease.

Polycystic kidney disease (PKD) is a genetic disorder characterized by aberrant renal epithelial cell proliferation and formation and progressive growth of numerous fluid-filled cysts within the kidneys. Previously, we showed that there is elevated Notch signaling compared to normal renal epithelial cells and that Notch signaling contributes to the proliferation of cystic cells. Quinomycin A, a bis-intercalator peptide, has previously been shown to target the Notch signaling pathway and inhibit tumor growth in cancer.

Ciclopirox olamine induces ferritinophagy and reduces cyst burden in polycystic kidney disease.

Despite the recent launch of tolvaptan, the search for safer polycystic kidney disease (PKD) drugs continues. Ciclopirox (CPX) or its olamine salt (CPX-O) is contained in a number of commercially available antifungal agents. CPX is also reported to possess anticancer activity.

Cross-talk between CDK4/6 and SMYD2 regulates gene transcription, tubulin methylation, and ciliogenesis.

Dysregulation of cyclin-dependent kinases 4 and 6 (CDK4/6) by unknown mechanisms is highly prevalent in human disease. In this study, we identify direct cross-talk between CDK4/6 and the epigenome via its previously unidentified substrate, SMYD2, a histone/lysine methyltransferase. CDK4/6 positively regulates the phosphorylation and enzymatic activity of SMYD2, while SMYD2 also positively regulates the expression of CDK4/6.

RNA helicase p68 inhibits the transcription and post-transcription of in ADPKD.

Autosomal dominant polycystic kidney disease (ADPKD) is caused by mutations of the and genes. Dysregulation of the expression of PKD genes, the abnormal activation of PKD associated signaling pathways, and the expression and maturation of miRNAs regulates cyst progression. However, the upstream factors regulating these abnormal processes in ADPKD remain elusive.

Epithelial Vasopressin Type-2 Receptors Regulate Myofibroblasts by a YAP-CCN2-Dependent Mechanism in Polycystic Kidney Disease.

Background: Fibrosis is a major cause of loss of renal function in autosomal dominant polycystic kidney disease (ADPKD). In this study, we examined whether vasopressin type-2 receptor (V2R) activity in cystic epithelial cells can stimulate interstitial myofibroblasts and fibrosis in ADPKD kidneys.

Methods: We treated gene knockout (KO) mice with dDAVP, a V2R agonist, for 3 days and evaluated the effect on myofibroblast deposition of extracellular matrix (ECM).

Adhesion GPCRs as a paradigm for understanding polycystin-1 G protein regulation.

Polycystin-1, whose mutation is the most frequent cause of autosomal dominant polycystic kidney disease, is an extremely large and multi-faceted membrane protein whose primary or proximal cyst-preventing function remains undetermined. Accumulating evidence supports the idea that modulation of cellular signaling by heterotrimeric G proteins is a critical function of polycystin-1. The presence of a cis-autocatalyzed, G protein-coupled receptor (GPCR) proteolytic cleavage site, or GPS, in its extracellular N-terminal domain immediately preceding the first transmembrane domain is one of the notable conserved features of the polycystin-1-like protein family, and also of the family of cell adhesion GPCRs.

Targeting the vasopressin type-2 receptor for renal cell carcinoma therapy.

Arginine vasopressin (AVP) and its type-2 receptor (V2R) play an essential role in the regulation of salt and water homeostasis by the kidneys. V2R activation also stimulates proliferation of renal cell carcinoma (RCC) cell lines in vitro. The current studies investigated V2R expression and activity in human RCC tumors, and its role in RCC tumor growth.

Metanephric organ culture.

Metanephric organ culture, or ex vivo embryonic kidney culture, was developed in the mid-twentieth century as a means to understand the development of the mammalian kidney and was used in early studies of polycystic kidney disease to explore mechanisms of renal cyst initiation by non-genetic factors. Following the identification of cystogenic genes, a resurgence of the use of metanephric organ culture occurred and has yielded insight into basic mechanisms of cystic dilation; facilitated identification of pathogenic pathways and potential therapeutic targets; and provided a system for evaluating therapeutic agents. This chapter provides detailed, step-by-step protocols with rationale and tips for the establishment, maintenance and treatment of metanephric organ cultures, and for performance of the most commonly employed secondary analyses of these cultures.

Human-Specific Abnormal Alternative Splicing of Wild-Type Induces Premature Termination of Polycystin-1.

Background: The major form of autosomal dominant polycystic kidney disease is caused by heterozygous mutations in , the gene that encodes polycystin-1 (PC1). Unlike genes in the mouse and most other mammals, human is unusual in that it contains two long polypyrimidine tracts in introns 21 and 22 (2.5 kbp and 602 bp, respectively; 97% cytosine and thymine).

A mutation affecting polycystin-1 mediated heterotrimeric G-protein signaling causes PKD.

Autosomal dominant polycystic kidney disease (ADPKD) is characterized by the growth of renal cysts that ultimately destroy kidney function. Mutations in the PKD1 and PKD2 genes cause ADPKD. Their protein products, polycystin-1 (PC1) and polycystin-2 (PC2) have been proposed to form a calcium-permeable receptor-channel complex; however the mechanisms by which they function are almost completely unknown.