PKD1 and PKD2 mRNA cis-inhibition drives polycystic kidney disease progression

Area of Science:

• Genetics
• Molecular Biology
• Nephrology

Background:

• Autosomal dominant polycystic kidney disease (ADPKD) is a common genetic disorder leading to kidney failure, primarily caused by heterozygous PKD1 mutations.
• Cyst formation in ADPKD occurs when the dosage of functional PKD1 falls below a critical threshold.
• Current therapeutic strategies lack methods to leverage the remaining functional allele or reverse PKD1 decline.

Purpose of the Study:

• To investigate a novel therapeutic strategy for ADPKD by targeting mRNA translation of PKD1 and PKD2.
• To determine if modifying the 3 étaire-UTR miR-17 binding element can enhance Polycystin-1 and Polycystin-2 levels and alleviate cyst growth.

Main Methods:

• Utilized cellular, ex vivo, and mouse models of PKD to assess the impact of modifying the 3 étaire-UTR miR-17 binding element in Pkd1 and Pkd2.
• Generated Pkd1^∆17 and Pkd2^∆17 alleles to eliminate the miR-17 binding motif.
• Assessed mRNA stability, Polycystin levels, cyst growth, proliferation, pCreb1 expression, and mitochondrial membrane potential in patient-derived ADPKD cultures.

Main Results:

• Eliminating the 3 étaire-UTR miR-17 binding motif in Pkd1^∆17 improved mRNA stability, increased Polycystin-1 levels, and reduced cyst growth.
• Pkd2 was also repressed by miR-17 via its 3 étaire-UTR, and Pkd2^∆17-induced Polycystin-2 derepression retarded cyst growth in Pkd1-mutant models.
• Acute blockade of Pkd1/2 cis-inhibition, even after cyst onset, attenuated murine PKD, and Pkd1^∆17/Pkd2^∆17 alleles reduced cyst size and proliferation in patient cultures.

Conclusions:

• Evading 3 étaire-UTR cis-interference and enhancing PKD1/2 mRNA translation represents a potentially mutation-agnostic approach to arresting ADPKD.
• This strategy offers a promising avenue for therapeutic intervention in ADPKD by targeting post-transcriptional regulation of key disease-driving genes.