Kidney Week

Abstract: TH-PO434

Ameliorative Effect of Anti-microRNA-21 Oligonucleotide Synthesized from Serinol Nucleic Acid on Animal and Human Models of Cystic Kidney Disease

Session Information

• Cystic Kidney Diseases: Clinical Assessment and Therapeutic Directions
  October 24, 2024 | Location: Exhibit Hall, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Genetic Diseases of the Kidneys

• 1201 Genetic Diseases of the Kidneys: Cystic

Authors

• Noda, Yuhei, Nagoya Daigaku Daigakuin Igakukei Kenkyuka Igakubu, Nagoya, Aichi, Japan

Yuhei Noda, MD

• Kato, Noritoshi, Nagoya Daigaku Daigakuin Igakukei Kenkyuka Igakubu, Nagoya, Aichi, Japan

Noritoshi Kato, MD, PhD

• Sato, Yuka, Nagoya Daigaku Daigakuin Igakukei Kenkyuka Igakubu, Nagoya, Aichi, Japan

Yuka Sato, MD, PhD

• Maeda, Kayaho, Nagoya Daigaku Daigakuin Igakukei Kenkyuka Igakubu, Nagoya, Aichi, Japan

Kayaho Maeda, MD, PhD

• Yamaguchi, Tamio, Suzuka Iryo Kagaku Daigaku, Suzuka, Mie, Japan

Tamio Yamaguchi, PhD

• Nagao, Shizuko, Fujita Ika Daigaku, Toyoake, Aichi, Japan

Shizuko Nagao, PhD

• Kosugi, Tomoki, Nagoya Daigaku Daigakuin Igakukei Kenkyuka Igakubu, Nagoya, Aichi, Japan

Tomoki Kosugi, MD, PhD

• Kamiya, Yukiko, Kobe Yakka Daigaku, Kobe, Hyogo, Japan

Yukiko Kamiya, PhD

• Asanuma, Hiroyuki, Nagoya Daigaku, Nagoya, Aichi, Japan

Hiroyuki Asanuma, DrPH

• Maruyama, Shoichi, Nagoya Daigaku Daigakuin Igakukei Kenkyuka Igakubu, Nagoya, Aichi, Japan

Shoichi Maruyama, MD, PhD

Background

Autosomal dominant polycystic kidney disease (ADPKD) is one of the most frequent single-gene disorders. It is characterized by the prolific emergence of renal cysts originating from the renal tubules, which proliferate within the bilateral kidneys due to the disturbance of manifold cellular processes. These aberrations include abnormal tubular epithelial cell proliferation, anomalous apoptotic events, and perturbations in mitochondrial metabolism. MicroRNAs (miRNAs) are endogenous small RNAs that regulate gene expression at the post-transcriptional level via sequence-specific hybridization. It has been reported that miR-21 is upregulated in ADPKD and is involved in cyst formation. In the present study, we assessed the effect for cystic disease using an anti-miRNA oligonucleotide targeting miR-21 synthesized from serinol.

Methods

In this study, we synthesized anti-miR-21 oligonucleotides from serinol nucleic acid to improve nuclease resistance and affinity to nucleic acid molecules and evaluated renal function and cyst growth in vivo mouse model. In vitro, anti-miR-21 oligonucleotides treatment was evaluated for inhibition of cyst enlargement in primary cultured renal tubular cells derived from ADPKD patient.

Results

In a mouse model of cystic kidney disease, systemically administered anti-miR-21 oligonucleotides accumulated mainly in the kidney, suggesting effective drug delivery to the diseased kidney, in addition to successfully suppressing renal cyst growth and improving renal function in mice. Anti-miR-21 oligonucleotides markedly suppressed miR-21 expression in microRNA in situ hybridization of miR-21 in the cystic kidney tissue. Western blotting of kidney tissue showed that it affected molecules associated with proliferation, mitochondrial metabolism, apoptosis, and fibrosis pathways characteristic in multiple cystic kidneys. In vitro, anti-miR-21 oligonucleotides significantly reduced cyst size and ameliorated the characteristic decrease in Ca2+ concentration in primary cultured human cells derived from ADPKD patient.

Conclusion

The favorable effect of anti-miR-21 oligonucleotide on cystic kidney model animals and human ADPKD cells showed its potential as a clinical therapeutic agent for ADPKD.