Search Results (194)

Autosomal dominant polycystic kidney disease (ADPKD), with a prevalence of approximately 1 in 1000, is the most common inherited cause of end-stage renal disease (ESRD). It is primarily caused by mutations in the PKD1 or PKD2 genes. Multiple studies have demonstrated that deficiency of polycystin proteins, dysregulation of signaling pathways, and activation of inflammatory factors contribute to the progression of ADPKD. The cAMP-targeting drug tolvaptan is currently the only approved therapy for ADPKD; however, its side effects and high cost have limited its widespread use. Meanwhile, mTOR inhibitors, AMPK-targeting agents, anti-inflammatory agents, and dietary interventions have shown promising results in treating ADPKD. Furthermore, the emergence of novel targets such as Notch3 and AURKA offers new directions for ADPKD therapy. This article aims to review the pathogenesis of ADPKD and current treatment advances, while exploring potential new targets for future research, hoping to provide a scientific theoretical foundation for disease management. Full article

Polycystic kidney disease (PKD), the most common inherited kidney disorder, is characterized by progressive cyst growth and eventual organ failure. Although aberrant innate immune activation is a recognized contributor to PKD progression, the underlying molecular mechanisms remain incompletely defined. Here, we showed that Pkd1 deletion increased TLR2 and MyD88 mRNA expression in renal epithelial cells, indicating enhanced innate immune priming. In vivo, administration of Pam3CSK4 (PAM), a synthetic TLR2 agonist, preferentially amplified pro-inflammatory and pro-fibrotic responses in Pkd1^RC/RC mice compared with wild-type controls, despite inducing similar signaling responses in vitro. Acute PAM treatment for one week rapidly enhanced NF-κB activation in cyst-lining epithelial cells, increased renal inflammation and cell proliferation, and was associated with activation of mTOR signaling and upregulation of c-Myc and Wnt proteins. Sustained PAM treatment further accelerated cyst expansion and renal fibrosis in PKD mice. Importantly, the endogenous TLR2 ligands decorin and biglycan were markedly elevated in human PKD kidneys, supporting the translational relevance of enhanced TLR2 signaling in disease progression. Together, these findings suggest that TLR2 signaling is an important contributor to PKD progression and a potential therapeutic target. Full article

The Golgi complex undergoes dynamic remodeling during the cell cycle, as ribbon unlinking in G2 is required for proper mitotic progression. Failure to fragment the ribbon leads to G2 arrest, whereas forced mitotic entry with intact ribbons results in multipolar spindle formation. Phosphorylation of the Golgi matrix protein GRASP65 at serine 277 (S277) in rat (S274 in human) by JNK2 is essential for ribbon unlinking, but its upstream regulation has remained unclear. Here, we generated and validated a phospho-specific antibody recognizing human GRASP65 phosphorylated at S274, enabling accurate detection of this modification. Using this tool, we identify protein kinase D2 (PKD2) as a critical upstream regulator required for GRASP65 phosphorylation and Golgi unlinking. GRASP65-S274 phosphorylation increases during G2 and is markedly reduced upon PKD2 inhibition or depletion, resulting in decreased Golgi unlinking and delayed G2/M transition. Conversely, PKD2-activating stimuli, including phorbol esters and nocodazole, enhance GRASP65 phosphorylation in a PKD2-dependent manner. These findings define PKD2 as a key regulator of the JNK2–GRASP65 signaling axis controlling Golgi disassembly at the G2/M transition. Moreover, the phospho-specific GRASP65 antibody described here provides a valuable tool to dissect upstream signaling mechanisms and to identify the initial triggers driving Golgi unlinking at G2 entry. Full article

Background: Inherited kidney diseases represent a genetically and clinically heterogeneous group of disorders affecting both pediatric and adult populations. Advances in next-generation sequencing (NGS) have improved diagnostic precision; however, genotype–phenotype correlations and diagnostic yield vary substantially across disease entities. Methods:We retrospectively evaluated 165 patients referred for genetic testing due to suspected inherited kidney disease. Patients were classified into three clinical groups: polycystic kidney disease, Alport syndrome, and other syndromic patients with inherited kidney diseases. Genetic analysis was performed using NGS with Human Phenotype Ontology–based gene filtering and included evaluation of both single-nucleotide variants and copy number variations. Results: Overall diagnostic yield differed markedly between groups. A molecular diagnosis was achieved in 71.4% of Alport patients, 41.0% of PKD patients, and 70.2% of patients in the Other syndromic group. In the Alport group, variants were identified exclusively in COL4A3, COL4A4, and COL4A5, with pathogenicity and gene involvement correlating with disease severity and the presence of extrarenal manifestations. The PKD group showed predominant involvement of PKD1, followed by PKHD1 and PKD2, while a substantial proportion of patients remained genetically negative, reflecting technical and biological complexity. The Other group exhibited pronounced genetic heterogeneity, with variants distributed across multiple genes involved in tubular, glomerular, metabolic, and ciliopathy-related pathways. Computational assessments demonstrated that several variants of uncertain significance (VUS) were located in functionally critical domains and were predicted to disrupt protein stability, intermolecular interactions, or conserved structural motifs, thereby supporting the biological plausibility of their potential pathogenic impact. Conclusions: Phenotype-driven NGS enables effective molecular diagnosis across diverse inherited kidney diseases while revealing disease-specific differences in diagnostic yield and genotype–phenotype correlations. Systematic inclusion of variants of uncertain significance and careful integration of genetic and clinical data are essential for accurate interpretation and long-term patient management. Collectively, this study enhances understanding of inherited kidney diseases and underscores the value of integrating comprehensive genomic and computational approaches into routine nephrogenetic practice. Full article

An accurate prediction of how strongly a drug binds to its target (where the drug will have the desired effect) is very important for drug discovery. It helps select the most promising compounds and saves money by doing fewer experiments. We present DTBAffinity, a multi-modal regression framework that integrates chemically meaningful ligand descriptors with diverse protein sequence features in a unified gradient-boosting model. The representation of ligands includes physicochemical and topological descriptors (RDKit and Mordred), structural keys (MACCS and FP4), circular fingerprints (ECFP/Morgan), and SMILES-derived features from iFeatureOmega. For proteins, thousands of sequence-derived descriptors (composition, autocorrelations, physicochemical profiles, and evolutionary indices) from iFeatureOmega are used, together with contextual embeddings from large protein language models (ESM-1b, ESM-2). The feature matrices are cleaned up, variance filtered, z-score scaled, and univariate selected before being concatenated and modeled with regularized XGBoost ensembles. We evaluate DTBAffinity on two kinase-centric datasets that are commonly used: Davis (30,056 interactions: pKd values) and KIBA (118,254 interactions: integrated affinity scores). Various metrics are used to measure the performance, such as MSE, R², Pearson/Spearman correlations, Concordance Index (CI), r_m², and AUPR. On Davis, DTBAffinity yields MSE = 0.1885, CI = 0.9102, and AUPR = 0.8112, and on KIBA, it gives MSE = 0.1540, CI = 0.8686, and AUPR = 0.8361; thus, it is better than the state-of-the-art baselines such as KronRLS, SimBoost, DeepDTA, and GraphDTA. The findings here imply that the combination of interpretable descriptors and contextual embeddings in a robust boosting framework is a great way to realize accurate, interpretable, and generalizable DTBA prediction. Full article

Globally, chronic kidney disease (CKD) affects over 800 million individuals and is characterized by significant genetic complexity. More than 600 genes are associated with hereditary kidney disease, which may manifest as isolated kidney issues or as part of a syndrome that also includes extrarenal manifestations. The aim of this study was to identify genetic variants in a group of ten patients who presented with clinical signs suggestive of genetic syndromes associated with CKD, or who were asymptomatic but had a positive family history of CKD. Extensive genetic testing (targeted gene panels and whole-exome sequencing—WES) identified a mutation in the PKD1 gene in 3 out of 10 cases. In one patient, a known mutation in the PKD2 gene was identified. Another four patients were diagnosed with Alport syndrome: three of these presented with de novo missense mutations in the COL4A5 gene, and one patient had a mutation in the COL4A3 gene. One patient was diagnosed with MODY5, caused by a known mutation in the HNF1B gene, and one patient was diagnosed with Bartter syndrome type 1, resulting from a known mutation in the SLC12A1 gene. We present genotype–phenotype correlations, highlighting the particularities of each patient within their family context. Our findings emphasize the importance of genotype–phenotype correlations in refining diagnosis, personalizing therapeutic management, and providing essential genetic counseling for at-risk relatives. Full article

Accurate plant recognition in desert grasslands is essential for ecological monitoring, yet existing models face critical limitations: poor generalization in complex natural environments and excessive computational demands for mobile deployment. This study proposes YOLOv11-PKD, a lightweight model integrating structured pruning and knowledge distillation for efficient desert grassland plant identification. First, we develop YOLOv11-STC, a high-capacity teacher model incorporating the SPPCSPC module for multi-scale feature extraction, Triplet Attention for spatial refinement, and a GSConv-based Slim Neck for optimized feature fusion. This architecture achieves 88.3% mAP50 on the DGPlant48 dataset, outperforming the baseline YOLOv11n by 6.8%. To enable edge deployment, we apply channel pruning guided by BatchNorm scaling factors, compressing the model by 19.75% in PParameters and 20% in GFLOPS (YOLOv11-Pruned: 79.5% mAP50, 4.7 MB). Subsequently, L2-based knowledge distillation recovers performance, yielding YOLOv11-PKD with 87.9% mAP50—approaching teacher-level accuracy—while maintaining 5.0 MB size, 2.150 M parameters, and 5.5 GFLOPS. The model is successfully deployed via a mobile application, achieving ~1 s response times for field-based plant identification. This work demonstrates a practical balance between accuracy and efficiency for resource-constrained ecological monitoring. Full article

Autosomal dominant polycystic kidney disease (ADPKD) is a genetic disorder primarily known for progressive kidney cysts, and it is the most common hereditary syndrome linked to intracranial aneurysms (IAs). Approximately 5–20% of ADPKD patients have IAs (versus ~3% in the general population). Key risk factors for IAs in ADPKD include a family history of aneurysmal subarachnoid hemorrhage (SAH), early-onset or poorly controlled hypertension, and possibly more severe kidney disease (e.g., large total kidney volume and reduced kidney function). The PKD1 and PKD2 mutations in ADPKD lead to polycystin-1/-2 dysfunction in vascular cells, causing intrinsic vessel wall weakness. This weakness—compounded by chronic hemodynamic stress and inflammation—predisposes ADPKD patients to aneurysm formation. Clinically, most aneurysms in ADPKD are small (<7 mm), asymptomatic, and located in the anterior cerebral circulation. Their growth and rupture risk appears similar to aneurysms in non-ADPKD patients; however, ruptures in ADPKD occur at younger ages, underscoring the need for vigilant management. This narrative review provides a nephrology-oriented overview of intracranial aneurysms in ADPKD, including pathophysiology, epidemiology, and clinical management. Key Messages: -ADPKD carries a higher prevalence of intracranial aneurysms (≈5–20%) than the general population (≈3%). Key risk factors include a family history of aneurysm/SAH, early or poorly controlled hypertension, and possibly advanced renal disease. -Guidelines support targeted rather than universal screening, mainly in patients with family history or prior SAH. -Non-contrast MRA is the preferred modality, usually initiated around age 30 in at-risk individuals. -Most aneurysms are small and asymptomatic; small lesions are monitored with BP control and imaging, while larger or high-risk aneurysms are treated prophylactically. -Broader screening remains debated. Future genetic insights may improve risk stratification, but current practice requires balancing rupture prevention against over screening. Full article

Autosomal dominant polycystic kidney disease (ADPKD), caused by mutations in PKD1 or PKD2, is characterized by progressive and exponential enlargement of renal and hepatic cysts. However, the epithelial dynamics that generate this growth pattern remain incompletely understood. Using Brainbow/Confetti multicolor clonal lineage tracing in developmental and adult-onset ADPKD mouse models, we show that polycystin-deficient epithelial cells initiate clonal expansion at early stages of tubule dilation and continue to expand throughout cyst progression. Concurrently, cyst-lining cells undergo a progressive transition from columnar to flattened morphology, which amplifies luminal enlargement independent of cell number. Integrating these measures, we developed a mathematical model demonstrating that the combination of this clonal expansion and epithelial cell shape remodeling is sufficient to produce the exponential growth trajectory observed in ADPKD. Together, these findings define the core epithelial mechanisms that drive cyst initiation and expansion, and may provide a mathematical framework for the emergent exponential growth of cysts. Full article

Background/Objectives: Autosomal dominant polycystic kidney disease (ADPKD) is a major cause of end-stage kidney disease (ESKD), accounting for approximately 5–10% of patients receiving dialysis worldwide. The large and numerous cysts in the liver and kidneys cause abdominal distention and poor appetite. Previous studies showed that renal arterial embolization (RAE) reduces total kidney volume (TKV), increases appetite, and improves quality of life. This article aims to evaluate the efficacy of RAE in increasing psoas muscle (PM) and paraspinal muscle (PS) mass in patients with polycystic kidney disease. Methods: A retrospective study was conducted from May 2016 to December 2020. Thirty-five patients with PKD and ESKD who received RAE were enrolled. The clinical data, including age, sex, body weight, abdominal circumference, and laboratory results, including albumin, creatinine, estimated glomerular filtration rate, and dialysis vintage, were collected. TKV was calculated with the ellipsoid formula method, and muscle mass was measured with bilateral PM and PS areas at the third lumbar level. The associated clinical, laboratory, and imaging data were compared before and after RAE. Results: There were 19 females and 16 males with a mean age of 59.9 for the final analysis. There were significant changes between baseline and 3-month, 6-month, 12-month after RAE, such as a decrease in TKV (4684 ± 3361 vs. 4079 ± 3456, 3675 ± 3401, 2459 ± 1706 mL, all p < 0.001), an increase in the PM area (12.6 ± 5.8 vs. 13.3 ± 5.7, 14.7 ± 6.9, 14.3 ± 7.1 cm², all p < 0.05), but no difference in body weight, body mass index, albumin, hemoglobin, creatinine, or estimated glomerular filtration rate. The increase in the PM and PS was more obvious in the sarcopenic group than in the non-sarcopenic group in the 12-month follow-up (p = 0.001 and 0.016 vs. p = 0.205 and 0.259). Conclusions: RAE effectively reduces TKV, increases PM and PS mass, and serves as a candidate to reverse muscle loss in patients with PKD. Full article

Cardiac hypertrophy is an important risk factor for heart failure and is often accompanied by contractile dysfunction. While hypertrophic growth contributes to disease progression, the underlying molecular mechanisms remain incompletely understood. A proposed contributor is a metabolic shift toward glucose uptake, suggesting that kinases regulating this process, such as protein kinase D1 (PKD1) and downstream target phosphatidylinositol 4-kinase IIIβ (PI4KIIIβ), might be effective targets to mitigate cardiac hypertrophy-induced contractile dysfunction. We investigated whether PI4KIIIβ inhibition downregulates enhanced glucose uptake in hypertrophic cardiomyocytes and thereby treats cardiac hypertrophy-induced contractile dysfunction. Hypertrophy was induced in cultured adult rat cardiomyocytes and human stem cell-derived cardiomyocytes using either phenylephrine (PE) or adenoviral PKD1 overexpression. PE-induced hypertrophy was associated with increased mRNA expression of BNP, activation of hypertrophic signaling, morphological alterations, enhanced protein synthesis and glucose uptake, and impaired contractile function. Treatment with the PI4KIIIβ inhibitor MI14 prevented and reversed PE-stimulated glucose uptake and contractile dysfunction, while hypertrophic signaling, cell size, and protein synthesis remained unaffected. Similar effects on glucose uptake were observed in the PKD1 overexpression model. These findings suggest that targeting myocardial substrate metabolism via the PI4KIIIβ pathway, rather than hypertrophic growth itself, could be a promising strategy to treat hypertrophy-induced contractile dysfunction. Full article

Background: Transjugular intrahepatic portosystemic shunt (TIPSS) outcomes in patients with moderate-to-severe pre-existing kidney disease (PKD, stages G3a–G4) remain poorly characterized. This study aimed to identify potential predictors of mortality specifically in patients with an eGFR 15–59 mL/min/1.73 m². Methods: We retrospectively analyzed 68 cirrhosis patients with PKD (eGFR < 60 mL/min/1.73 m²) undergoing a TIPSS between April 2021 and April 2024. Clinical outcomes, renal function changes, and 12-month survival were assessed. Statistical analyses included paired t-tests with false discovery rate adjustment and Kaplan–Meier survival analysis to identify potential predictors of mortality. Results: The cohort (mean age 61.0 ± 8.3 years, 83.8% male, 79.4% with PKD G3a–G3b) showed modest improvement in renal function (creatinine 1.93 to 1.75 mg/dL, p = 0.031), though this biochemical change did not predict survival. Overall mortality was 36.8% (95% CI: 25.4–49.5%) at mean follow-up of 6.7 months. Traditional severity scores (MELD, Child–Turcotte–Pugh) showed no significant association with survival (p > 0.05 for all comparisons). In exploratory analyses, mortality was significantly higher in patients with the following: (1) uncontrolled diabetes before a TIPSS (55.2% vs. 25.9%; RR 2.35, 95% CI: 1.08–5.15, p = 0.032); (2) post-TIPSS infection (70.0% vs. 31.0%; HR 5.44, 95% CI: 1.54–19.23, p = 0.009); and (3) post-procedural cardiac events (85.7% vs. 31.1%; p = 0.005). These associations persisted after false-discovery rate adjustment but require prospective validation given the modest sample size and wide confidence intervals. Conclusions: In this exploratory single-center study of patients with moderate PKD undergoing a TIPSS, we observed associations between mortality and pre-TIPSS poorly controlled diabetes, infections, and cardiac events. These hypothesis-generating findings suggest potential areas for future research. Prospective multi-center studies are needed to validate these associations and determine whether interventions targeting these factors improve outcomes. Full article

Autosomal Dominant Polycystic Kidney Disease (ADPKD) is caused by mutations in PKD1 or PKD2 genes, encoding polycystin-1 (PC1) or polycystin-2 (PC2), respectively, characterized by excessive cell proliferation and fluid secretion, resulting in renal cyst formation and growth. PC1 and PC2 form a complex localized on the plasma membrane, endoplasmic reticulum, and primary cilia. PC2 is a non-selective cation channel which, in renal epithelial cells, contributes to calcium transport and signaling. It has been previously shown in renal cells that high external calcium increases whole-cell currents likely mediated by PC2. In this study, we explored the possibility that the Calcium Sensing Receptor (CaSR) is involved in the functional regulation of PC2. To test this hypothesis, human conditionally immortalized Proximal Tubular Epithelial cells, isolated from urine sediments, wt or with stably downregulated PKD1 (PC1KD) or PKD2 (PC2KD) were used. Interestingly, CaSR and PC2 co-immunoprecipitated and Proximity Ligation Assay demonstrated a direct physical interaction at endogenous protein levels. Membrane potential measurements demonstrated that selective CaSR activation, elicited by the calcimimetic R568, caused plasma membrane depolarization, consistent with the modulation of PC2-mediated cation currents, which was significantly lower in PC2KD with respect to wt and PC1KD cells. To conclude, this study provides evidence for a functional coupling of CaSR and PC2, which might be relevant for therapeutic strategies to correct dysregulations occurring in ADPKD. Full article

Alzheimer’s disease (AD) is a worldwide problem due to the lack of effective therapy and accurate methods for timely diagnosis. The complexity of AD’s pathophysiology complicates the development of effective therapeutic agents, as most drugs act on only one therapeutic target, bypassing others. The design and development of multifunctional agents capable of altering metal ion-induced abnormalities, oxidative stress, and toxic beta amyloid (Aβ) aggregates is of interest. Herein, we report the first boron dipyrromethene (BODIPY) based bifunctional copper chelator with clioquinol, BDP-CLQ, capable of both optical detection of Aβ fibrils and copper chelation, with multiple anti-AD properties. Foremost, BDP-CLQ demonstrated a 3-fold and 5-fold fluorescence increase at 650 nm and 565 nm in the presence of Aβ and effective copper chelation (pK_d = 16.6 ± 0.3). In addition, BDP-CLQ demonstrated a potent inhibition of Aβ aggregation, reduction in Aβ-induced stiffness of neuronal cells, and antioxidant activity. BDP-CLQ is the first BODIPY-based fluorescent probe with multiple anti-AD activities, as well as the first clioquinol-based probe capable of Aβ optical visualization. This study demonstrates the prospects of the development of clioquinol-based theranostic probes since this allows combining several promising anti-AD actions in a single molecule and developing multi-targeted drugs. Full article

Host factors play critical roles in viral IRES-mediated translation by modulating the efficiency and specificity of viral protein synthesis. In this study, we used small interfering RNA (siRNA) treatment to silence and plasmid-based expression to overexpress PKD1L3 and USP31. Silencing PKD1L3 and USP31 suppressed IRES activity in FMDV and CSFV RNAs, whereas the overexpression of PKD1L3 did not have a significant effect, and USP31 overexpression resulted in only a modest increase in CSFV-IRES activity. Silencing PKD1L3 significantly reduced EMCV-IRES activity but had no significant effect on HCV- or DENV-IRES activity, and silencing USP31 had no significant effect on the activities of these three IRESs. Notably, the combined overexpression of PKD1L3 and USP31 significantly suppressed HCV-IRES activity, suggesting potential context-dependent interactions. These findings indicated that PKD1L3 and USP31 contribute more prominently to CSFV-, FMDV-, and EMCV-IRES-mediated translation than to HCV- or DENV-IRES-driven translation. Collectively, our results provide new insights into the host factors involved in IRES-mediated viral translation, establish a foundation for future in vivo studies to elucidate the specific roles of PKD1L3 and USP31 during viral infection, and indicate potential strategies for mitigating these viruses. Full article