microRNA-17 family promotes polycystic kidney disease progression through modulation of mitochondrial metabolism

Area of Science:

• Genetics
• Molecular Biology
• Nephrology

Background:

• Autosomal dominant polycystic kidney disease (ADPKD) is the leading inherited cause of end-stage renal disease.
• Identifying novel therapeutic targets is crucial for managing ADPKD progression.

Purpose of the Study:

• To investigate the role of microRNA-17 (miR-17) in ADPKD pathogenesis.
• To evaluate miR-17 as a potential therapeutic target for ADPKD.

Main Methods:

• Analysis of miR-17 expression in mouse and human ADPKD kidney cysts.
• Genetic deletion of the miR-17∼92 cluster in ADPKD mouse models.
• Inhibition of miR-17 using anti-miR therapies in vivo and in vitro.
• Investigation of the molecular mechanisms involving c-Myc and Pparα.

Main Results:

• miR-17 is upregulated in kidney cysts of both mouse and human ADPKD.
• Deletion of the miR-17∼92 cluster significantly reduced cyst proliferation and disease progression in multiple ADPKD mouse models.
• Anti-miR-17 treatment effectively attenuated cyst growth in short-term and long-term studies.
• miR-17 inhibition suppressed proliferation and cyst growth in primary human ADPKD cyst cultures.
• Mechanistically, c-Myc upregulates miR-17, which inhibits oxidative phosphorylation and promotes proliferation by repressing Pparα.

Conclusions:

• The miR-17 family represents a promising therapeutic target for ADPKD.
• miR-17-mediated inhibition of mitochondrial metabolism is a novel mechanism contributing to ADPKD progression.