Modulation of polycystic kidney disease by non-coding RNAs

Abstract

Purpose of review: microRNAs (miRNAs) are a class of small, evolutionarily conserved, non-coding RNAs (ncRNAs) that function as inhibitors of post-transcriptional mRNA expression. They are implicated in the pathogenesis of numerous diseases, including many common kidney conditions. In this review, we focus on how miRNAs impact autosomal dominant polycystic kidney disease (ADPKD) progression. We also discuss the feasibility of the emerging novel antisense oligonucleotides (ASOs) drug class, which includes anti-miRNA drugs, for the treatment of ADPKD.

Recent findings: Aberrant miRNA expression is observed in multiple PKD murine models and human ADPKD samples. Gain and loss-of-function studies have directly linked dysregulated miRNA activity to kidney cyst growth. The most comprehensively studied miRNA in PKD is the miR-17 family, which promotes PKD progression through the rewiring of cyst metabolism and by directly inhibiting PKD1 and PKD2 expression. This discovery has led to the development of an anti-miR-17 drug for ADPKD treatment. Other miRNAs such as miR-21, miR-193, and miR-214 are also known to regulate cyst growth by modulating cyst epithelial apoptosis, proliferation, and interstitial inflammation.

Summary: miRNAs have emerged as novel pathogenic regulators of ADPKD progression. Anti-miR-based drugs represent a new therapeutic modality to treat ADPKD patients.

Figure 1.. Biogenesis of miRNAs.

Transcription miRNA genes by RNA Polymerase II enzyme creates a long RNA transcript called primary-miRNA (pri-miRNA). The pri-miRNA folds into a secondary structure comprised of double-stranded RNA (dsRNA) and hairpin loops. The microprocessor complex (DROSHA and DGCR8) cleaves the pri-miRNA into a shorter pre-miRNAs. The pre-miRNAs are exported out of the nucleus by Exportin-5. In the cytoplasm, the RNAse III enzyme DICER processes the pre-miRNAs to form the 22~ nucleotide double-stranded mature miRNA. The mature miRNA guides the catalytic activity of Argonaute proteins, thus creating the RNA induced silencing complex (RISC).

Figure 2.. Mechanism by which miR-21 and miR-17~92 promote cyst growth.

A. The cAMP/CREB pathway promotes miR-21 transcription via its unique promoter located in the intron of Tmem49. The mature miR-21 inhibits PDCD4 activity resulting in reduced apoptosis of cystic epithelial cells. miR-21 also inhibits PPARa mediated oxidative phosphorylation. RG-012 is an anti-miR that inhibits miR-21 activity. B. The miR-17 miRNA family is derived from the miR-17~92 and two other paralogous miRNA clusters. c-Myc promotes the transcription of the miR-17~92 cluster. The miR-17 family consists of miR-17, miR-20a, miR-20b, miR-106a, miR-106b and miR-93. These miRNAs have the same seed sequence and directly inhibit PKD1, PKD2, and PPARa. RGLS4326 is an anti-miR drug that inhibits the miR-17 family.

Figure 3.

Unmodified RNA is quickly degraded by nucleases and can evoke an intense immune reaction if administered systemically. However, the phosphate backbone, a ribose sugar, and the nitrogenous nucleotide base of RNAs can be chemically modified to overcome these issues. Some of the common chemical modifications used to impart ‘drug-like’ properties are shown.

Figure 4.. Strategies to modulate miRNA activity.

There are three main categories for pharmacologically modulating miRNA activity. A. miRNA mimics are synthetic versions of endogenous miRNAs. They amplify or restore miRNA activity. B. Anti-miR oligonucleotides are ASOs that repress the endogenous miRNA(s). They have complementary sequences to the miRNA of interest. Therefore, they bind to the mature miRNA, sequestering them away from the target mRNAs. Thus, the target mRNA network is de-repressed. C. Target site blockers (TSBs) are ASO that prevent the repression of a specific mRNA target of miRNA. They function by blocking miRNAs from binding to their target mRNAs.