miRNA profiling of a mutation-negative PKD cohort reveals PKD1/PKD2 ADPKD shared signatures and differences

Autosomal dominant polycystic kidney disease (ADPKD) is mainly caused by mutations in PKD1 or PKD2 genes, but a subgroup of patients has no detectable mutation and remains understudied. We profiled microRNAs (miRNAs) in this mutation-negative group and compared them with PKD1, PKD2, and healthy controls.
Targeted miRNA profiling was used to measure miRNAs expression. We tested five prespecified contrasts using Welch’s two-sided t-test (p < 0.05). For interpretation, experimentally supported miRNA–mRNA interactions were assembled and visualized into networks.
miR-92a was found upregulated across all patient-control groups. Interestingly, the mutation-negative cohort showed the broadest deregulation, pointing toward higher expression together with enhanced extracellular-matrix remodeling. PKD1 vs controls displayed a more restricted number of deregulated miRNAs; when PKD1 was compared directly with the mutation-negative group, we observed selective reductions, most notably miR-134-5p. PKD2 vs controls showed fewer changes overall but overlapped with the core signature observed in other groups and no miRNAs met the threshold in PKD2 vs mutation-negative.
The results indicate that miRNA dysregulation is present in the absence of identifiable PKD1/PKD2 mutations, supporting the idea of common pathways and highlighting the translational potential of miRNAs as biomarkers or therapeutic targets.
Autosomal dominant polycystic kidney disease (ADPKD) is a genetic condition in which many cysts grow in the kidneys, leading to loss of kidney function over time. Most patients have changes in two genes, called PKD1 or PKD2, but some people show signs of the disease even though no mutation can be found. These patients are difficult to diagnose and are not well studied. In this work, we measured small molecules called microRNAs (miRNAs) in the blood of ADPKD patients. miRNAs are important to control cellular processes by regulating genes turning them “on” or “off.” By comparing people with PKD1 mutations, PKD2 mutations, those without detectable mutations, and healthy volunteers, we looked for patterns that might explain how the disease behaves in different groups. We found that one miRNA, called miR-92a-3p, was increased in all patients with ADPKD, no matter which gene was affected. This suggests it may play a central role in the disease and could be useful as a blood-based marker. Patients without detectable mutations showed the largest number of changes in their miRNAs, indicating that their disease biology may be more complex than previously thought. When we looked at how these miRNAs interact with the genes they regulate, we found that many of them are involved in cell growth, tissue repair, and changes in the kidney’s supporting structure, which are all processes known to take part in cyst formation. Overall, our findings could help to explain why ADPKD develops and progresses, even in patients without identified gene mutations. They also suggest new potential biomarkers and biological pathways that could be further explored for earlier diagnosis or future treatments.