Ameliorative Effect of an Anti-MicroRNA-21 Oligonucleotide on Animal and Human Models of Cystic Kidney Disease

Area of Science:

• Biochemistry
• Genetics
• Molecular Biology

Background:

• Hereditary cystic kidney diseases, including autosomal dominant polycystic kidney disease (ADPKD), are ciliopathies linked to primary cilia dysfunction.
• Aberrant microRNA expression, particularly miR-21 upregulation driven by cAMP signaling, contributes to cystogenesis in ADPKD.
• Existing treatments for cystic kidney diseases are limited, necessitating novel therapeutic strategies.

Purpose of the Study:

• To develop and evaluate a novel anti-miR-21 oligonucleotide synthesized from serinol nucleic acid (Anti-miR-21-SNA) for enhanced anti-miRNA activity.
• To investigate the therapeutic efficacy of Anti-miR-21-SNA in reducing cyst growth in vitro and in vivo models of cystic kidney disease.

Main Methods:

• Systemic administration of Anti-miR-21-SNA in a mouse model of cystic kidney disease.
• In vitro treatment of primary kidney cells from ADPKD patients with Anti-miR-21-SNA.
• Assessment of kidney size, blood urea nitrogen levels, hepatotoxicity, intracellular cAMP, and Ca2+ concentration.

Main Results:

• Anti-miR-21-SNA demonstrated effective accumulation in kidneys, significantly reducing kidney size and blood urea nitrogen levels in vivo without causing hepatotoxicity.
• In vitro, Anti-miR-21-SNA treatment decreased cyst volume and intracellular cAMP levels while increasing Ca2+ concentration in ADPKD cells.
• Mechanistic investigations revealed involvement of mitochondrial metabolism, apoptosis, and fibrosis pathways.

Conclusions:

• Anti-miR-21-SNA treatment shows significant promise as a therapeutic strategy for managing cystic kidney diseases.
• The study highlights the potential of targeting miR-21 with SNA-based oligonucleotides for treating ADPKD and related ciliopathies.