Polycystic Kidney Disease Mechanisms and Therapeutic Strategies

Polycystic kidney disease (PKD) encompasses a group of genetic disorders characterised by the progressive formation of fluid‐filled cysts within the renal parenchyma, leading to loss of functional nephrons and eventual renal failure. The most common form, autosomal dominant PKD (ADPKD), arises from mutations in PKD1 or PKD2 that encode polycystin-1 and polycystin-2, proteins integral to mechanosensation, calcium homeostasis and mitochondrial metabolism. Disruption of polycystin signalling perturbs intracellular calcium levels, drives aberrant cAMP/ERK pathway activation and promotes epithelial proliferation. Emerging evidence has highlighted a profound metabolic reprogramming in cystic epithelia, with enhanced glycolysis, altered fatty acid oxidation and glutamine dependency, which sustain rapid cell growth. Therapeutic strategies have evolved from non-specific blockade of renal cyst expansion towards targeted molecular interventions. These include gene therapy approaches delivering functional polycystin fragments to mitochondria, antisense oligonucleotides aimed at microRNA regulators of proliferation, and small-molecule inhibitors of cyst expansion pathways such as mTOR, AMPK and metabolic enzymes. A precision-medicine framework is taking shape, combining genetic diagnosis with pathway-specific treatments to delay cyst growth and preserve renal function.

Research from Nature Portfolio

Recent studies have demonstrated that a minimal C-terminal fragment of polycystin-1, when introduced into animal models of ADPKD, localises to mitochondria and interacts with key redox enzymes to restore metabolic balance and suppress cystogenesis. This work provides proof of principle for fragment-based gene therapy to correct underlying mitochondrial dysfunction. In parallel, the development of first-in-class oligonucleotide inhibitors targeting the miR-17 family has shown efficacy in displacing pathological microRNAs, de-repressing endogenous PKD1/PKD2 expression and attenuating cyst growth in both human cell cultures and multiple rodent models. Together, these advances underscore the therapeutic potential of combining subcellular targeting and post-transcriptional regulation to modify disease progression.

Polycystic Kidney Disease Mechanisms and Therapeutic Strategies publication trend

The graph below shows the total number of articles in polycystic kidney disease mechanisms and therapeutic strategies across all publications each year (not limited to Nature Index journals).

Technical terms

Polycystin-1 (PC1): large transmembrane protein encoded by PKD1, involved in mechanosensation, calcium signalling and mitochondrial function.

Polycystin-2 (PC2): calcium‐permeable ion channel subunit encoded by PKD2, essential for ciliary and endoplasmic reticulum calcium homeostasis.

Autosomal dominant polycystic kidney disease (ADPKD): inherited disorder marked by renal cyst formation due to PKD1 or PKD2 mutations.

cAMP/ERK pathway: signalling cascade where cyclic AMP activates B-Raf and ERK kinases, driving cell proliferation.

Metabolic reprogramming: adaptive shifts in energy metabolism, including increased glycolysis and altered mitochondrial substrate use, sustaining cyst growth.

miR-17 family: group of microRNAs that post-transcriptionally regulate genes involved in proliferation and metabolism in PKD.

Oligonucleotide inhibitor: synthetic strand designed to bind and neutralise specific RNA molecules, modulating gene expression.

References

1. The C-terminal tail of polycystin-1 suppresses cystic disease in a mitochondrial enzyme-dependent fashion. Nature Communications (2023).
2. Discovery and preclinical evaluation of anti-miR-17 oligonucleotide RGLS4326 for the treatment of polycystic kidney disease. Nature Communications (2019).
3. Polycystin Channel Complexes. Annual Review of Physiology (2023).
4. Inhibition of Aerobic Glycolysis Attenuates Disease Progression in Polycystic Kidney Disease. PLOS ONE (2016).
5. Calcium Restriction Allows cAMP Activation of the B-Raf/ERK Pathway, Switching Cells to a cAMP-dependent Growth-stimulated Phenotype*. Journal of Biological Chemistry (2004).
6. Dissection of metabolic reprogramming in polycystic kidney disease reveals coordinated rewiring of bioenergetic pathways. Communications Biology (2018).
7. Polycystin-2 is an essential ion channel subunit in the primary cilium of the renal collecting duct epithelium. eLife (2018).