Autosomal Dominant Polycystic Kidney Disease Research Articles

Heterozygous loss of function variants in IFT140 are associated with polycystic kidney disease.

Autosomal dominant polycystic kidney disease (ADPKD) affects 1 in 1000 adults. Most cases result from causative PKD1 or PKD2 variants. HNF1B, GANAB and ALG9 variants are also associated with ADPKD. Recent evidence indicates that monoallelic loss-of-function (LoF) IFT140 variants are a cause for non-syndromic ADPKD. We describe 368 patients with IFT140 LoF variants and a spectrum of phenotypic findings that support the association of IFT140 with PKD. We reviewed patients with an unknown cause for their cystic disease and those with heterozygous LoF IFT140 variants classified as pathogenic or likely pathogenic from a cohort that received genetic testing using a panel of 385 renal disease-associated genes. IFT140 LoF variants were significantly enriched in patients with cystic disease when compared with those without cystic disease. A cystic phenotype was reported in 223 of the 368 (60.6%) individuals harboring an IFT140 LoF variant, 98% of which had no other identified cause for their cystic disease. Of 122 unique LoF IFT140 variants identified, 56 (46%) were frameshift, 38 (31%) nonsense, 22 (18%) splice site and 6 (5%) exon-level deletions. Only six IFT140 individuals were reported with end-stage kidney disease, consistent with observed milder clinical presentations in IFT140-related PKD. This study offers further evidence for the involvement ofLoF IFT140 variants in PKD, particularly when no additional molecular etiology has been identified.

The Impact of Autosomal Dominant Polycystic Kidney Disease in Children: A Nephrological, Nutritional, and Psychological Point of View.

Autosomal dominant polycystic kidney disease (ADPKD) is a hereditary disorder characterized by the formation of numerous fluid-filled cysts in the kidneys, leading to progressive renal failure and various extrarenal complications, including hypertension. This review explores the genetic basis of ADPKD, including emerging evidence of epigenetic mechanisms in modulating gene expression and disease progression in ADPKD. Furthermore, it proposes to examine the pathological characteristics of this condition at the nephrological, cardiovascular, nutritional, and psychological levels, emphasizing that the follow-up of patients with ADPKD should be multidisciplinary from a young pediatric age.

Native nephrectomies in patients with autosomal dominant polycystic kidney disease: retrospective cohort study.

Approximately 1 in 5 patients with autosomal dominant polycystic kidney disease (ADPKD) will undergo a native nephrectomy in their lifetime. These can be emergent or planned and the indications can range from space for kidney transplant, pain, hematuria and frequent urinary tract infections (UTIs). Due to the diverse nature of presentations, there is a lack of certainty about outcomes and optimal management. This study aimed to evaluate preoperative indications and perioperative/postoperative complications in this patient cohort. This retrospective review included 41 patients with ADPKD who underwent unilateral or bilateral nephrectomy in a single hospital between 2010 and 2020. We collected data on patient demographics, surgical indications, histological results and postoperative complications. We sourced this information using the hospital's patient medical records. The main indications for nephrectomy were pain (39.5%) and bleeding (41.8%). Further indications included recurrent UTIs (16.3%), space for transplantation (27.9%), query malignancy (4.7%) and compressive gastropathy (2.3%). With regard to side, 55.8% were right-sided, 23.3% were left-sided, and 20.9% were bilateral. Seven percent of nephrectomy specimens demonstrated malignancy. Postoperative morbidity included requiring blood transfusion and long hospital stay. Thirty-seven percent of patients received a postoperative blood transfusion. There was no immediate or postoperative mortality associated with any of the cases reviewed. In conclusion, this study demonstrates that native nephrectomy remains a safe operation for patients with ADPKD. Although further research is needed into, transfusion protocols, adjunctive therapies, such as TAE and research into timing of nephrectomy are still needed.

Single-Base Substitution Causing Dual-Exon Skipping Event in PKD2 Gene: Unusual Molecular Finding from Exome Sequencing in a Patient with Autosomal Dominant Polycystic Kidney Disease.

Background: Pathogenic variants in the Polycystic Kidney Disease 2 (PKD2) gene are associated with Autosomal Dominant Polycystic Kidney Disease (ADPKD) in approximately 30% of cases. In recent years, the high-throughput sequencing techniques have significantly increased the number of variants identified in affected patients. Here, we described the peculiar effect of a PKD2 splicing variant, the c.1717-2A>G, identified in an Italian male patient with ADPKD. This variant led to the unusual and rare skipping of two consecutive exons, causing a large in-frame deletion. Methods: The genetic evaluation of the patient was performed using the Next-Generation Sequencing (NGS) assay Clinical Exome Solution® (SOPHiA Genetics). Bioinformatics analysis was performed using the SOPHiA DDM platform (SOPHiA Genetics). Prediction of pathogenicity was carried out by integrating several in silico tools. RNA evaluation was performed to test the effect of the variant on the PKD2 splicing using a Reverse-Transcription PCR coupled with cDNA sequencing. Results: NGS revealed the presence of the PKD2 c.1717-2A>G variant that lies in the canonical splice site of intron 7. This rare variant was predicted to have a significant impact on the splicing, proved by the RNA-based analysis. We identified the presence of a transcript characterised by the simultaneous skipping of exons 8 and 9, with a retained reading frame and the merging of exons 7-10. Conclusions: We described for the first time a dual-exon skip event related to the presence of a single-base substitution in the PKD2 gene in an ADPKD-affected patient. We assumed that the molecular basis of such a rare mechanism lies in the specific order of intron removal. The finding represents novel evidence of an alternative and unusual splicing mechanism in the PKD2 gene, adding insights to the pathogenesis of the ADPKD.

Potential Add-On Benefits of Dietary Intervention in the Treatment of Autosomal Dominant Polycystic Kidney Disease.

Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited cause of renal failure. The pathogenesis of the disease encompasses several pathways and metabolic alterations, including the hyperactivation of mTOR and suppression of AMPK signaling pathways, as well as mitochondrial dysfunction. This metabolic reprogramming makes epithelial cyst-lining cells highly dependent on glucose for energy and unable to oxidize fatty acids. Evidence suggests that high-carbohydrate diets may worsen the progression of ADPKD, providing the rationale for treating ADPKD patients with calorie restriction and, in particular, with ketogenic dietary interventions, already used for other purposes such as in overweight/obese patients or in the treatment of refractory epilepsy in children. Preclinical studies have demonstrated that calorie restriction may prevent and/or slow disease progression by inducing ketosis, particularly through increased beta-hydroxybutyrate (BHB) levels, which may modulate the metabolic signaling pathways altered in ADKPK. In these patients, although limited, ketogenic intervention studies have shown promising beneficial effects. However, larger and longer randomized controlled trials are needed to confirm their tolerability and safety in long-term maintenance and their additive role in the therapy of polycystic kidney disease.

Atypical noncontiguous TSC2/PKD1 gene deletions presenting as tuberous sclerosis/polycystic kidney disease contiguous gene syndrome.

Tuberous sclerosis complex (TSC) and autosomal dominant polycystic kidney disease (ADPKD) are genetically distinct disorders typically associated with pathogenic variants in TSC1 and TSC2 for the former and PKD1 and PKD2 for the latter. TSC2 and PKD1 lie adjacent to each other, and large deletions comprising both genes lead to TSC2/PKD1 contiguous gene deletion syndrome (CGS). In this study, we describe a young female patient exhibiting symptoms of TSC2/PKD1 CGS in which genetic analysis disclosed two noncontiguous partial gene deletions in TSC2 and PKD1 that putatively are responsible for the manifestations of the syndrome. Further analysis revealed that both deletions appear to be de novo on the maternal chromosome, presumably with a germline origin. Despite extensive analysis, no maternal chromosomal rearrangement triggering these pathogenic variants was detected. This case elucidates a unique pathogenesis for TSC2/PKD1 CGS, diverging from the common contiguous deletions typically observed, marking the first reported instance of TSC2/PKD1 CGS caused by independent, functionally significant partial gene deletions.

Chronic endothelial dopamine receptor stimulation improves endothelial function and hemodynamics in autosomal dominant polycystic kidney disease

Altered polycystin-mediated endothelial flow mechanosensitivity contributes to the development of hypertension and cardiovascular complications in patients with autosomal dominant polycystic kidney disease (ADPKD). Stimulation of endothelial type 5 dopamine receptors (DR5) can acutely compensate for the endothelial consequences of polycystin deficiency, but the chronic impact of this approach must be evaluated in ADPKD. Nineteen patients with ADPKD on standard of care therapy were randomized to receive a 2-month treatment with the DR agonist rotigotine using transdermal patches, nine at 2 mg/24hours and ten at 4 mg/24hours or while ten were untreated. Rotigotine at the dose of 4 mg/24hours significantly increased nitric oxide release (nitrite levels from 10±30 to 46±34 nmol/L) and radial artery endothelium-dependent flow-mediated dilatation (from 16.4±6.3 to 22.5±7.3%) in response to hand skin heating. Systemic hemodynamics were not significantly modified but aplanation tonometry showed that rotigotine at 4 mg/24hours reduced aortic augmentation index and pulse pressure without affecting carotid-to femoral pulse wave velocity. Plasma creatinine and urea, urinary cyclic AMP, which contributes to cyst growth in ADPKD and copeptin, a surrogate marker of vasopressin, were not affected by rotigotine. In mice with a specific deletion of polycystin-1 in endothelial cells, chronic infusion of the peripheral DR5 agonist fenoldopam also improved mesenteric artery flow-mediated dilatation and reduced blood pressure. Thus, our study demonstrates that in patients with ADPKD, chronic administration of rotigotine improves conduit artery endothelial function through the restoration of flow-induced nitric oxide release as well as hemodynamics suggesting that endothelial DR5 activation may represent a promising pharmacological approach to prevent cardiovascular complications of ADPKD.

Analysis of serum proteomic in cats with polycystic kidney disease-1 gene mutation

Feline autosomal dominant polycystic kidney disease (PKD) is common in Persian and Persian-cross cats. This study aims to investigate proteins that can be potential biomarkers for early disease diagnosis in cats with PKD1 heterozygous gene mutations and compare them with chronic kidney disease cats and normal wild-type cats. Thirty-three client-owned cats of variable breeds (ten PKD1 gene mutation cats, twelve wild-type cats with normal blood profiles, and eleven wild-type cats with chronic renal disease) were enrolled in this study. This study used serum-based proteomic profiling analysis in cats. Abdominal ultrasounds were examined in all cats. Proteomic analysis was conducted by matrix-assisted laser desorption ionization time-of-flight (MALDI-TOF) mass spectrometry and liquid chromatography-tandem mass spectrometry (LC-MS/MS). One hundred and fifty-nine proteins were significantly differentially expressed between each group. The proteins identified in this study are known to regulate the apoptosis pathway. The apoptosis regulator Bcl-2 (BCL2) was overexpressed in the chronic kidney disease (CKD) group, while apoptotic peptidase activating factor 1 (APAF1) and BCL2-associated X apoptosis regulator (BAX) were only expressed in the PKD group. Ingenuity pathway analysis revealed that proteins uniquely expressed in the PKD group were linked to the Wnt signaling pathway and MAPK pathway. Asparagine synthetase domain-containing and secreted frizzled-related proteins were interesting proteins that should be studied further for the possibility of a candidate protein for disease detection. The proteomic profiles identified in this study could be used as potential novel biomarkers for the early detection of PKD in cats.

Cilia-enriched oxysterol 7β,27-DHC is required for polycystin ion channel activation

Polycystin-1 (PC-1) and PC-2 form a heteromeric ion channel complex that is abundantly expressed in primary cilia of renal epithelial cells. This complex functions as a non-selective cation channel, and mutations within the polycystin complex cause autosomal dominant polycystic kidney disease (ADPKD). The spatial and temporal regulation of the polycystin complex within the ciliary membrane remains poorly understood. Using both whole-cell and ciliary patch-clamp recordings, we identify a cilia-enriched oxysterol, 7β,27-dihydroxycholesterol (DHC), that serves as a necessary activator of the polycystin complex. We further identify an oxysterol-binding pocket within PC-2 and showed that mutations within this binding pocket disrupt 7β,27-DHC–dependent polycystin activation. Pharmacologic and genetic inhibition of oxysterol synthesis reduces channel activity in primary cilia. In summary, our findings reveal a regulator of the polycystin complex. This oxysterol-binding pocket in PC-2 may provide a specific target for potential ADPKD therapeutics.

Additional Relevant Intracranial Findings in Persons Screened with MR for Intracranial Aneurysms

BackgroundRadiological screening for intracranial aneurysms (IAs) may identify other relevant intracranial findings. We investigated their prevalence on MR in persons screened for IAs. MethodsWe included all persons who were screened for the presence of IAs with brain MRI/MRA between 1996 and 2022 because of a family history of aneurysmal subarachnoid haemorrhage (aSAH) or autosomal dominant polycystic kidney disease (ADPKD). We reviewed radiology reports of initial and repeated brain MR to identify additional intracranial findings that needed follow-up or treatment, or carried a risk of becoming symptomatic. ResultsWe included 766 persons (positive family history of aSAH: n = 681; ADPKD: n = 85) who had 1446 MRI/MRAs. At initial screening, 49 additional relevant intracranial findings were reported in 47 persons (6.1%, 95% CI 4.7–8.1%). Of all included persons, 338 (44%) underwent one (n = 154) or more (n = 184) follow-up screenings (total MRI/MRAs at follow-up: n = 680). In 15/338 persons (4.4%, 95% CI 2.7–7.2%), 16 new additional relevant findings were reported at a median follow-up duration of 10 years (IQR 5–12). ConclusionsPersons who are counselled for screening for IAs should be informed that there is a six percent chance of identifying an additional finding that requires follow-up or treatment, or may become symptomatic. Additionally, after 10-year follow-up screening there is a four percent chance of identifying a new additional relevant finding. The impact of such findings on quality of life needs further study.

Performance of [18F]FDG PET/CT in Diagnosing Cyst Infections in Patients with Autosomal Dominant Polycystic Kidney Disease: A Systematic Review and a Bivariate Meta-Analysis.

Fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography ([18F]FDG PET/CT) has been suggested as a useful imaging method for diagnosing cyst infections in patients with autosomal dominant polycystic kidney disease (ADPKD). The aim of this article is to provide evidence-based data in this setting. A systematic literature review (exploring several bibliographic databases) and a bivariate meta-analysis were carried out to calculate the pooled diagnostic performance of [18F]FDG PET/CT in diagnosing probable cyst infection in ADPKD. Ten studies (282 PET/CT scans and 249 patients) were included in the analysis. The pooled sensitivity and specificity of [18F]FDG PET/CT in this setting were 84.6% (95% confidence interval: 75.4-90.7) and 94.9% (95% confidence interval: 72.6-99.2), respectively, without statistical heterogeneity or significant publication bias. [18F]FDG PET/CT significantly changed patient management in more than half of ADPKD patients with suspected cyst infection. [18F]FDG PET/CT has high performance in diagnosing probable cyst infections in ADPKD patients with an impact on management in the majority of patients. Although more studies are warranted, the provided evidence-based data are an important step towards the integration of [18F]FDG PET/CT in clinical and diagnostic guidelines on probable cyst infection in ADPKD patients.

Kidney Stone Disease and Progression Risk in Autosomal Dominant Polycystic Kidney Disease: A Post Hoc Analysis of OVERTURE

Kidney Stone Disease and Progression Risk in Autosomal Dominant Polycystic Kidney Disease: A Post Hoc Analysis of OVERTURE

Chromodomain Y-like (CDYL) inhibition ameliorates acute kidney injury in mice by regulating tubular pyroptosis.

Acute kidney injury (AKI) is a common disease, but lacking effective drug treatments. Chromodomain Y-like (CDYL) is a kind of chromodomain protein that has been implicated in transcription regulation of autosomal dominant polycystic kidney disease. Benzo[d]oxazol-2(3H)-one derivative (compound D03) is the first potent and selective small-molecule inhibitor of CDYL (KD = 0.5 μM). In this study, we investigated the expression of CDYL in three different models of cisplatin (Cis)-, lipopolysaccharide (LPS)- and ischemia/reperfusion injury (IRI)-induced AKI mice. By conducting RNA sequencing and difference analysis of kidney samples, we found that tubular CDYL was abnormally and highly expressed in injured kidneys of AKI patients and mice. Overexpression of CDYL in cisplatin-induced AKI mice aggravated tubular injury and pyroptosis via regulating fatty acid binding protein 4 (FABP4)-mediated reactive oxygen species production. Treatment of cisplatin-induced AKI mice with compound D03 (2.5 mg·kg-1·d-1, i.p.) effectively attenuated the kidney dysfunction, pathological damages and tubular pyroptosis without side effects on liver or kidney function and other tissue injuries. Collectively, this study has, for the first time, explored a novel aspect of CDYL for tubular epithelial cell pyroptosis in kidney injury, and confirmed that inhibition of CDYL might be a promising therapeutic strategyagainst AKI.

Primer on fibroblast growth factor 7 (FGF 7)

Fibroblast growth factor 7 (FGF7), also known as keratinocyte growth factor (KGF), is an important member of the FGF family that is mainly expressed by cells of mesenchymal origin while affecting specifically epithelial cells. Thus, FGF7 is widely expressed in diverse tissues, especially in urinary system, gastrointestinal tract (GI-tract), respiratory system, skin, and reproductive system. By interacting specifically with FGFR2-IIIb, FGF7 activates several downstream signal pathways, including Ras, PI3K-Akt, and PLCs. Previous studies of FGF7 mutants also have implicated its roles in various biological processes including development of essential organs and tissue homeostasis in adults. Moreover, more publications have reported that FGF7 and/or FGF7/FGFR2-IIIb-associated signaling pathway are involved in the progression of various heritable or acquired human diseases: heritable conditions like autosomal dominant polycystic kidney disease (ADPKD) and non-syndromic cleft lip and palate (NS CLP), where it promotes cyst formation and affects craniofacial development, respectively; acquired non-malignant diseases such as chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF), mucositis, osteoarticular disorders, and metabolic diseases, where it influences inflammation, repair, and metabolic control; and tumorigenesis and malignant diseases, including benign prostatic hyperplasia (BPH), prostate cancer, gastric cancer, and ovarian cancer, where it enhances cell proliferation, invasion, and chemotherapy resistance. Targeting FGF7 pathways holds therapeutic potential for managing these conditions, underscoring the need for further research to explore its clinical applications. Having more insights into the function and underlying molecular mechanisms of FGF7 is warranted to facilitate the development of effective treatments in the future.Here, we discuss FGF7 genomic structure, signal pathway, expression pattern during embryonic development and in adult organs and mutants along with phenotypes, as well as associated diseases.

Automatically Detecting Pancreatic Cysts in Autosomal Dominant Polycystic Kidney Disease on MRI Using Deep Learning.

Pancreatic cysts in autosomal dominant polycystic kidney disease (ADPKD) correlate with PKD2 mutations, which have a different phenotype than PKD1 mutations. However, pancreatic cysts are commonly overlooked by radiologists. Here, we automate the detection of pancreatic cysts on abdominal MRI in ADPKD. Eight nnU-Net-based segmentation models with 2D or 3D configuration and various loss functions were trained on positive-only or positive-and-negative datasets, comprising axial and coronal T2-weighted MR images from 254 scans on 146 ADPKD patients with pancreatic cysts labeled independently by two radiologists. Model performance was evaluated on test subjects unseen in training, comprising 40 internal, 40 external, and 23 test-retest reproducibility ADPKD patients. Two radiologists agreed on 52% of cysts labeled on training data, and 33%/25% on internal/external test datasets. The 2D model with a loss of combined dice similarity coefficient and cross-entropy trained with the dataset with both positive and negative cases produced an optimal dice score of 0.7 ± 0.5/0.8 ± 0.4 at the voxel level on internal/external validation and was thus used as the best-performing model. In the test-retest, the optimal model showed superior reproducibility (83% agreement between scan A and B) in segmenting pancreatic cysts compared to six expert observers (77% agreement). In the internal/external validation, the optimal model showed high specificity of 94%/100% but limited sensitivity of 20%/24%. Labeling pancreatic cysts on T2 images of the abdomen in patients with ADPKD is challenging, deep learning can help the automated detection of pancreatic cysts, and further image quality improvement is warranted.

Importance of IFT140 in Patients with Polycystic Kidney Disease Without a Family History

Recently, the monoallelic loss-of-function IFT140 variant was identified as a causative gene for autosomal dominant polycystic kidney disease (ADPKD). In patients with polycystic kidneys who have a positive family history, >90% have pathogenic variants in PKD1 or PKD2, whereas only 1% have IFT140. However, approximately 40% of patients with polycystic kidneys without a family history do not have any pathogenic variants in PKD1 and PKD2. We conducted a comprehensive genetic analysis of 157 adult patients with polycystic kidneys whose parents did not have evident polycystic kidneys. We sequenced up to 92 genes associated with inherited cystic kidney disease, including IFT140. Of the 157 patients, 7 (4.5%) presented with monoallelic loss-of-function variants in the IFT140 gene, 51 (32.5%) with pathogenic variants in the PKD1 or PKD2 gene, and 7 (4.5%) with pathogenic variants in other genes related to inherited kidney cystic disease. The proportion of monoallelic loss-of-function IFT140 variants in this cohort was higher than that in previously reported cohorts with polycystic kidneys who had a positive family history. None of the patients with monoallelic loss-of-function IFT140 variants had polycystic liver disease (PLD). Furthermore, patients with IFT140 pathogenic variants had a significantly smaller kidney volume and a remarkably higher estimated glomerular filtration rate (eGFR) than those with PKD1 pathogenic variants (P= 0.01 and 0.03, respectively). Because the phenotype of polycystic kidneys caused by the IFT140 gene is mild, parental kidney disease may be overlooked. Therefore, patients without a positive family history are more likely to carry pathogenic variants in IFT140.

Overview of clinical status, treatment, and long-term outcomes of pediatric autosomal-dominant polycystic kidney disease: a nationwide survey in Taiwan

This retrospective study investigated the incidence, medication use, and outcomes in pediatric autosomal-dominant polycystic kidney disease (ADPKD) using Taiwan's National Health Insurance Research Database (NHIRD). A 1:4 matched control group of individuals included in the NHIRD during the same period was used for comparative analyses. A total of 621 pediatric patients were identified from 2009 to 2019 (mean age, 9.51 ± 6.43 years), and ADPKD incidence ranged from 2.32 to 4.45 per 100,000 individuals (cumulative incidence, 1.26–1.57%). The incidence of newly developed hypertension, anti-hypertensive agent use, nephrolithiasis, and proteinuria were significantly higher in the ADPKD group than the non-ADPKD group (0.7 vs. 0.04, 2.26 vs. 0.30, 0.4 vs. 0.02, and 0.73 vs. 0.05 per 100 person-years, respectively). The adjusted hazard ratios for developing hypertension, proteinuria, nephrolithiasis and anti-hypertensive agent use in cases of newly-diagnosed pediatric ADPKD were 12.36 (95% CI 4.92–31.0), 13.49 (95% CI 5.23–34.79), 13.17 (95% CI 2.48–69.98), and 6.38 (95% CI 4.12–9.89), respectively. The incidence of congenital cardiac defects, hematuria, urinary tract infections, gastrointestinal diverticulosis, dyslipidemia, and hyperuricemia were also higher in the ADPKD group. Our study offers valuable insights into the epidemiology of pediatric ADPKD in Taiwan and could help in formulating guidelines for its appropriate management.

Prevalence of spinal meningeal diverticula in autosomal dominant polycystic kidney disease.

Autosomal dominant polycystic kidney disease (ADPKD) patients develop cysts in the kidneys, liver, spleen, pancreas, prostate and arachnoid spaces. In addition, spinal meningeal diverticula have been reported. To determine whether spinal meningeal diverticula are associated with ADPKD, we compare their prevalence in ADPKD subjects to a control cohort without ADPKD. ADPKD subjects and age-and gender-matched controls without ADPKD undergoing abdominal MRI from mid-thorax to the pelvis from 2003 to 2023 were retrospectively evaluated for spinal meningeal diverticula by 4 blinded observers. Prevalence of spinal meningeal diverticula in ADPKD was compared to control subjects, using t-test and correlated with clinical and laboratory data, and magnetic resonance imaging (MRI) features, including cyst volumes and cyst counts. Identification of spinal meningeal diverticula in ADPKD (n=285, median age, 47 [37,56]; 54% female) and control (n=285, median age, 47 [37,57]; 54% female) subjects had high inter-observer agreement (Pairwise Cohen kappa=0.74). Spinal meningeal diverticula were observed in 145 of 285 (51%) ADPKD subjects compared with 66 of 285 (23%) control subjects without ADPKD (p<0.001). Spinal meningeal diverticula in ADPKD were more prevalent in women (98 of 153 [64%]) than men (47 of 132 [36%], p<0.001). The mean number of spinal meningeal diverticula per affected ADPKD subject was 3.6 + 2.9 compared to 2.4 + 1.9 in controls with cysts (p<0.001). The median volume/interquartile range (IQR, 25%/75%) of spinal meningeal diverticula was 400 mm3 (210, 740) in ADPKD compared to 250 mm3 (180, 440) in controls (p<0.001). Mean/SD spinal meningeal diverticulum diameter was greater in the sacrum (7.3 + 4.1 mm) compared to thoracic (5.4 + 1.8 mm) and lumbar spine (5.8 + 2.0 mm), p<0.001, suggesting that that hydrostatic pressure contributed to enlargement. ADPKD has a high prevalence of spinal meningeal diverticula, particularly in women. ADPKD = Autosomal dominant polycystic kidney disease.

Polycystin-1 loss of function increases susceptibility to atrial fibrillation through impaired DNA damage response.

The increasing prevalence of atrial fibrillation (AF) and chronic kidney diseases highlights the need for a deeper comprehension of the molecular mechanisms linking them. Mutations in PKD1, the gene encoding Polycystin-1 (PKD1 or PC1), account for 85% of autosomal dominant polycystic kidney disease (ADPKD) cases. This disease often includes cardiac complications such as AF. In cardiomyocytes, PC1 deletion reduces hypertrophic response to pressure overload but promotes baseline ventricular dysfunction, while deletion in fibroblasts ameliorates post-myocardial infarction fibrosis. Despite its known cardiac impact, the role of PC1 in atrial cardiomyocytes and arrhythmias is less understood. Here, we sought to investigate the role of PC1 in AF. We used intracardiac programmed stimulation and optical mapping to evaluate AF inducibility in two mouse models, Pkd1 R3277C, which recapitulates human ADPKD progression, and cardiomyocyte-specific Pkd1 deletion, and their respective controls. Isolated adult mouse atrial cardiomyocytes, human iPSC-derived atrial cardiomyocytes (hiPSC-aCM), and HL-1 cells served as in vitro cellular models. Molecular mechanisms were evaluated using optical mapping and molecular and biochemical approaches. Loss-of-function PC1 mutations significantly increased AF susceptibility in vivo and facilitated local reentry in ex vivo left atrial appendages. Comprehensive in vitro experiments supported a direct effect of PC1 in atrial cardiomyocytes. PC1-deficient monolayers exhibited increased arrhythmic events, escalating into reentrant spiral waves post-tachypacing. Transcriptomics analysis revealed PC1-dependent regulation of DNA repair, with PC1 deficiency leading to increased DNA damage under stress. PARP1 inhibitors or nicotinamide riboside, which counteract DNA damage-related metabolic consequences, reduced in vitro arrhythmias PC1-deficient monolayers. Overexpression of the C-terminus of PC1 had the opposite effects in DNA repair genes, suggesting its regulatory effects in atrial cardiomyocytes through retinoblastoma/E2F. Analyses of human atrial tissue from non-ADPKD patients showed reduced levels of mature PC1, suggesting a broader relevance of impaired PC1 in AF. Impaired PC1 increases in vivo AF inducibility under programmed electrical stimulation and promotes in vitro arrhythmias in hiPSC-aCM and HL-1 cells. Our findings indicate that PC1 protects against DNA damage to reduce AF susceptibility.

Activation of Polycystin-1 Signaling by Binding of Stalk-derived Peptide Agonists.

Polycystin-1 (PC1) is the membrane protein product of the PKD1 gene whose mutation is responsible for 85% of the cases of autosomal dominant polycystic kidney disease (ADPKD). ADPKD is primarily characterized by the formation of renal cysts and potential kidney failure. PC1 is an atypical G protein-coupled receptor (GPCR) consisting of 11 transmembrane helices and an autocatalytic GAIN domain that cleaves PC1 into extracellular N-terminal (NTF) and membrane-embedded C-terminal (CTF) fragments. Recently, signaling activation of the PC1 CTF was shown to be regulated by a stalk tethered agonist (TA), a distinct mechanism observed in the adhesion GPCR family. A novel allosteric activation pathway was elucidated for the PC1 CTF through a combination of Gaussian accelerated molecular dynamics (GaMD), mutagenesis and cellular signaling experiments. Here, we show that synthetic, soluble peptides with 7 to 21 residues derived from the stalk TA, in particular, peptides including the first 9 residues (p9), 17 residues (p17) and 21 residues (p21) exhibited the ability to re-activate signaling by a stalkless PC1 CTF mutant in cellular assays. To reveal molecular mechanisms of stalk peptide-mediated signaling activation, we have applied a novel Peptide GaMD (Pep-GaMD) algorithm to elucidate binding conformations of selected stalk peptide agonists p9, p17 and p21 to the stalkless PC1 CTF. The simulations revealed multiple specific binding regions of the stalk peptide agonists to the PC1 protein including an "intermediate" bound yet inactive state. Our Pep-GaMD simulation findings were consistent with the cellular assay experimental data. Binding of peptide agonists to the TOP domain of PC1 induced close TOP-putative pore loop interactions, a characteristic feature of the PC1 CTF signaling activation mechanism. Using sequence covariation analysis of PC1 homologs, we further showed that the peptide binding regions were consistent with covarying residue pairs identified between the TOP domain and the stalk TA. Therefore, structural dynamic insights into the mechanisms of PC1 activation by stalk-derived peptide agonists have enabled an in-depth understanding of PC1 signaling. They will form a foundation for development of PC1 as a therapeutic target for the treatment of ADPKD.