miR-21, Mediator, and Potential Therapeutic Target in the Cardiorenal Syndrome

Abstract

Oligonucleotide-based therapies are currently gaining attention as a new treatment option for relatively rare as well as common diseases such as cardiovascular disease. With the remarkable progression of new sequencing technologies, a further step towards personalized precision medicine to target a disease at a molecular level was taken. Such therapies may employ antisense oligonucleotides to modulate the expression of both protein coding and non-coding RNAs, such as microRNAs. The cardiorenal syndrome (CRS) is a complex and severe clinical condition where heart and renal dysfunction mutually affect one another. The underlying mechanisms remain largely unknown and current treatments of CRS are mainly supportive therapies which slow down the progression of the disease, but hardly improve the condition. The small non-coding RNA, microRNA-21 (miR-21), is dysregulated in various heart and kidney diseases and has been repeatedly suggested as therapeutic target for the treatment of CRS. Impressive preclinical results have been achieved by an antisense oligonucleotide-based therapy to effectively block the pro-fibrotic traits of miR-21. Since microRNA-mediated pathways are generally very well-conserved, there is considerable commercial interest with regards to clinical translation. In this review, we will summarize the role of miR-21 within the heart-kidney axis and discuss the advantages and pitfalls of miR-21 targeting therapeutic strategies in CRS.

Keywords: antisense-oligonucleotides; cardiorenal syndrome (CRS); miR-21; miR-21 inhibitor; microRNA; non-coding RNA (ncRNA).

Figure 1

The role of miR-21 in cardiorenal syndrome. The underlying mechanisms of CRS are still unclear, and the current classification system for CRS is based on the clinical phenotype. Based on the primary organ dysfunction, CRS can be categorized into five subtypes. Under certain stress conditions (hypertension, LPS, or inflammation), the miR-21 is upregulated in (A) cardiac or (B) renal fibroblast and induces fibrosis. MiR-21 can also be transported by microvesicles to other cell types to induce fibrosis. (C) In SLE, the miR-21 is upregulated in both B and T cells which induces strong inflammation. Treatment of miR-21 ASOs could significantly alleviate the fibrosis and, therefore, improve the cardiac and renal function.