Timing Matters

Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common monogenic diseases, affecting nearly 12.5 million people worldwide and representing the fourth leading cause of kidney failure in adults. Although mutations in PKD1 and PKD2 are well-established genetic causes of ADPKD, the post-transcriptional regulatory networks that govern disease initiation, progression, and the transition from early cystogenesis to advanced CKD remained incompletely understood. In this issue of Kidney360, Sharma et al.¹ presents a comprehensive longitudinal characterization of the renal microRNA (miRNA) expression in Pkd1^RC/RC mice, offering a temporal roadmap of miRNAs dysregulated across the natural history of ADPKD progression.

miRNAs are short, noncoding RNA molecules (approximately 22 nucleotides) that function as post-transcriptional regulators of gene expression. Dysregulation of miRNA networks has been implicated in multiple aspects of ADPKD pathobiology. Early evidence for a role of miRNAs in ADPKD came from Patel et al., showing that genetic ablation of the miRNA-processing enzyme Dicer in the renal tubule resulted in tubular and glomerular cyst formation in mice.² Dicer regulates a kidney-enriched family of miRNAs, including the miR-200 family, which has been shown to regulate Pkd1 expression in the kidney. Thus, loss of Dicer led to reduced miR-200 expression and derepression of Pkd1, which was proposed to be the cause of the cystogenesis.

Subsequent work identified the miR-17 approximately 92 cluster as a key driver of cyst epithelial proliferation and metabolic reprogramming in ADPKD.³ In parallel, miR-21 has been shown to promote cyst growth through suppression of epithelial apoptosis,⁴ whereas miR-214 attenuates inflammation and disease progression via effects on the cyst microenvironment.⁵ Beyond individual miRNAs, unbiased profiling studies of kidney tissue and urinary exosomes from patients with ADPKD have identified circulating miRNAs that correlate with eGFR and total kidney volume, supporting their potential utility as biomarkers of disease severity.⁶ However, most studies have been cross-sectional, restricted to single time points, and conducted predominantly in rapidly progressive experimental models that do not reflect the slow, decades-long course of human ADPKD. As a result, the field lacks a temporal framework to distinguish early, disease-specific miRNA alterations from secondary changes associated with advancing CKD.

To address this critical gap Sharma et al. used the Pkd1^RC/RC mouse, a hypomorphic PKD model harboring two copies of the clinically relevant p.Arg3277Cys variant of Pkd1.¹ These mice develop slowly progressive cystic disease with preserved renal function for at least 1 year, closely mimicking the adult ADPKD phenotype.⁷ The authors performed miRNA sequencing and mRNA-seq on kidneys from Pkd1^RC/RC and wild-type mice at 1 and 12 months, integrated these datasets to identify functionally relevant miRNA-mRNA target pairs, and validated their findings with quantitative PCR and protein expression analyses. They identified 41 differentially expressed miRNAs at 1 month (early disease) and 181 at 12 months (advanced disease) and classified them into six groups based on temporal expression patterns. Target genes of miRNAs dysregulated from early stages encoded proteins implicated, not surprisingly, in cell proliferation, but also unexpectedly in α-ketoglutarate (α-KG) transport. Those dysregulated at late stages encoded proteins involved in pro-inflammatory and metabolic processes. The study further validated that expression of the organic anion transporters, NaDC3 and Oat1, was decreased. This was accompanied by an increase in urine concentration, fractional excretion, and kidney tissue levels of α-KG in the Pkd1^RC/RC mice, but because NaDC3 and Oat1 normally mediate organic anion secretion, the mechanism remains unclear.

These results highlight several areas where additional experiments could refine temporal and mechanistic interpretation. For instance, intermediate time points for sequencing were not included (6 months was used, but only for phenotyping), which means the precise temporal kinetics of miRNA transitions remain to be fully resolved. The reliance on bulk tissue sequencing precludes cell-type–specific miRNA contributions. Higher resolution approaches such as single-cell or spatial transcriptomic would clarify whether the observed changes originate from cyst-lining epithelia, interstitial cells, or infiltrating immune cells. While the integrated miRNA-mRNA analysis is informative, miRNA target prediction inherently carries a high false-positive rate, and the functional annotations, although plausible, remain correlative rather than causal. The α-KG findings, while intriguing, would benefit from genetic or pharmacologic manipulation of the implicated transporters to establish causality. Finally, the comparison with human ADPKD data is inherently constrained by the lack of human kidney tissue from early disease stages, a limitation the authors appropriately acknowledge but one that nonetheless tempers the translational extrapolation.

The study by Sharma et al. moves the ADPKD field forward in several meaningful ways. By establishing a temporal hierarchy of miRNA dysregulation, the work provides a conceptual framework for distinguishing primary, disease-initiating regulatory events from secondary CKD-related changes, a distinction with direct therapeutic implications. The identification of 30 novel differentially expressed miRNAs at early stages that have not been reported in other PKD models or human studies opens new avenues for mechanistic investigation. In addition, the discovery that α-KG transport dysregulation is an early feature, potentially driven by miRNA-mediated suppression of Slc13a3 (NaDC3) and Slc22a6 (Oat1), connects post-transcriptional regulation to metabolic reprogramming, a rapidly expanding area of PKD research. This finding aligns with emerging evidence of abnormal glutamine metabolism in ADPKD and could point toward α-KG as a urinary biomarker for early disease detection, a prospect that warrants prospective validation in young patients with ADPKD.

Perhaps the most exciting dimension of this work is its implications for miRNA-based therapeutics in ADPKD. The strategy of using anti–miR-17 oligonucleotide for therapy was based on foundational studies demonstrating that the miR-17 approximately 92 cluster drives cyst proliferation and suppresses PKD1 and PKD2 expression.⁸ Farabursen, a next-generation anti–miR-17 oligonucleotide with preferential kidney distribution, has shown remarkable promise in clinical trials. The completed phase 1b multiple-ascending dose trial showed that farabursen dose-dependently increased urinary polycystin-1 and polycystin-2 levels and appeared potentially to halt height-adjusted total kidney volume growth over 4 months compared with placebo. The results, presented at ASN Kidney Week 2025,⁹ also demonstrated that ADPKD genotype and Mayo Class did not influence treatment response, suggesting broad applicability. A phase 3 pivotal trial is planned and will be the first such trial of an antagomir for ADPKD.

Intriguingly, Sharma et al. did not observe significant dysregulation of miR-17 approximately 92 cluster members in the Pkd1^RC/RC model, a finding that likely reflects the slowly progressive nature of this hypomorphic model, its mixed genetic background, and the specific time points and statistical criteria employed. This observation does not diminish the therapeutic rationale for miR-17 inhibition but rather highlights that the miRNA landscape of ADPKD is far more complex than any single cluster. Indeed, recent work by Lakhia et al. has demonstrated that disruption of a mere six-nucleotide miR-17 seed match within the PKD1 3′ untranslated region is sufficient to stabilize Pkd1 mRNA and reduce cyst growth in vivo, providing elegant proof-of-concept for precision oligonucleotide strategies that restore polycystin dosage.¹⁰

The temporal framework established by Sharma et al. has direct implications for the design of future miRNA-based interventions. If early-stage miRNAs regulate fundamentally different biologic processes than late-stage miRNAs as this study suggests, then a “one-size-fits-all” approach to miRNA therapeutics may be suboptimal. Early intervention targeting miRNAs that drive cell proliferation and metabolic reprogramming may be most effective at preventing cyst initiation, while later-stage targeting of inflammatory and fibrotic miRNA networks could slow CKD progression. The study thus supports the emerging concept of stage-adapted, combination miRNA therapy in ADPKD.

Disclosures

Disclosure forms, as provided by each author, are available with the online version of the article at http://links.lww.com/KN9/B654.

Author Contributions

Conceptualization: Alan S.L. Yu.

Writing – original draft: Duuamene Nyimanu.

Writing – review & editing: Duuamene Nyimanu, Alan S.L. Yu.

Funding

None.