Ciliopathies

Autosomal Dominant Polycystic Kidney Disease (ADPKD) is a systemic ciliopathy resulting from loss-of-function mutations in the PKD1 and PKD2 genes, which encode polycystin-1 (PC1) and polycystin-2 (PC2), respectively. PC1 and PC2 regulate mechanosensation, calcium signaling, and key pathways controlling tubular epithelial structure and function. Loss of PC1/PC2 disrupts calcium homeostasis, elevates cAMP, and activates proliferative cascades such as PKA-B-Raf-MEK-ERK, mTOR, and Wnt, driving cystogenesis via epithelial proliferation, impaired apoptosis, fluid secretion, and fibrosis. Recent evidence also implicates novel signaling axes in ADPKD progression including, the Hippo pathway, where dysregulated YAP/TAZ activity enhances c-Myc-mediated proliferation; the stimulator of interferon genes (STING) pathway, which is activated by mitochondrial DNA release and linked to NF-κB-driven inflammation and fibrosis; and the TWEAK/Fn14 pathway, which mediates pro-inflammatory and pro-apoptotic responses via ERK and NF-κB activation in tubular cells. Mitochondrial dysfunction, oxidative stress, and maladaptive extracellular matrix remodeling further exacerbate disease progression. A refined understanding of ADPKD's complex signaling networks provides a foundation for precision medicine and next-generation therapeutics. This review gathers recent molecular insights and highlights both established and emerging targets to guide targeted treatment strategies in ADPKD.

Autosomal Dominant Polycystic Kidney Disease (ADPKD) is the most common inherited kidney disease, characterized by the progressive development of multiple kidney cysts, leading to a gradual decline in kidney function. ADPKD is also the fourth leading cause of kidney failure (KF) in adults. In addition to kidney manifestations, ADPKD is associated with various extrarenal features, including liver cysts, cardiovascular abnormalities, intracranial aneurysms, and chronic pain with significant impact on patients' quality of life. While several disease-modifying agents have been tested in ADPKD, tolvaptan remains the only approved drug by the US Food and Drug Administration. The Mayo Imaging Classification is currently the most practical tool for predicting rate of kidney disease progression in ADPKD. This review provides a comprehensive overview of ADPKD, focusing on its genetics, pathophysiology, clinical presentation, management, and prognostic tools. Advances in diagnostic imaging and genetic testing have improved the early detection of ADPKD, allowing better classification of patients and prediction of KF. The review also discusses current therapeutic approaches to ADPKD, including tolvaptan, a vasopressin V2-receptor antagonist. Additionally, we address specific issues in children and pregnant individuals with ADPKD. Despite substantial progress in understanding ADPKD, there is a large need for additional effective treatments and prognostic markers to provide a more personalized care for these patients.

Autosomal dominant polycystic kidney disease (ADPKD) is the most prevalent genetic kidney disorder, affecting over 10 million individuals worldwide. Cystic expansion typically progresses to kidney failure and also involves the liver with limited treatment options. Pathogenic variants in PKD1 or PKD2 account for 85%-90% of cases. Genetic re-expression of Pkd1 or Pkd2 has been shown to partially reverse key characteristics of the disease phenotype in mice. Despite advancements in understanding the genetic basis, it remains unclear whether correcting pathogenic variants can effectively prevent, modify, or reverse the disease. Additionally, the feasibility of genome editing as a treatment remains largely unexplored. In this study, we employed CRISPR base editing to correct representative pathogenic PKD1 variants selected from a patient cohort, achieving precise and efficient editing in vitro. Correction of a murine missense variant (c.6646C>T (R2216W)) in primary renal epithelial cells increased polycystin-1 expression and reduced the endoplasmic reticulum stress marker sXBP1. In vivo, base editor delivery to the c.6646C>T (R2216W) knockin mouse enabled correction of the pathogenic variant, resulting in a significant reduction in liver cysts. These findings provide the first evidence that genome editing may ameliorate key features of ADPKD, opening promising therapeutic perspectives for affected patients and their families.

IntroductionAutosomal Dominant Polycystic Kidney Disease (ADPKD) is caused by mutations in PKD1 or PKD2 and is the most common single-gene disorder resulting in kidney failure. Since deletion of either Pkd1 or Pkd2 in mice is embryonically lethal, conditional alleles have become indispensable tools for studying the pathobiology of ADPKD and for preclinical testing. The rapidity of cyst formation in Pkd1 conditional mice depends on the timing of gene inactivation, but this has never been systematically studied for Pkd2. Here, we characterize the kinetics of cystogenesis in a Pkd2 conditional mouse model and identify associated alterations in gene expression.MethodsUsing a conditional mouse model, we inactivated Pkd2 at different postnatal stages and characterized the severity of cyst formation. Additionally, we performed RNA-sequencing analysis to identify gene expression changes associated with Pkd2 loss in males and females.ResultsThere is a similar developmental switch in Pkd2 conditional mice with delayed cyst formation after Pkd2 inactivation at or beyond postnatal day 14. Like Pkd1 models, cystogenesis is associated with differential expression of genes involved in metabolism, cell proliferation, and immune response. We confirm that sex is a key modifier of ADPKD progression with differences in disease severity occurring in the context of significant transcriptional differences between males and females that are independent of the Pkd2 genotype.ConclusionsPkd2 conditional mice are a useful model for understanding ADPKD pathogenesis and for testing therapeutics. Our data highlight the importance of sex as a biological variable that should be considered in any study design using orthologous mouse models with late Pkd2 inactivation.