MicroRNA-21 Silencing in Diabetic Nephropathy: Insights on Therapeutic Strategies

Abstract

In diabetes, possibly the most significant site of microvascular damage is the kidney. Due to diabetes and/or other co-morbidities, such as hypertension and age-related nephron loss, a significant number of people with diabetes suffer from kidney diseases. Improved diabetic care can reduce the prevalence of diabetic nephropathy (DN); however, innovative treatment approaches are still required. MicroRNA-21 (miR-21) is one of the most studied multipotent microRNAs (miRNAs), and it has been linked to renal fibrosis and exhibits significantly altered expression in DN. Targeting miR-21 offers an advantage in DN. Currently, miR-21 is being pharmacologically silenced through various methods, all of which are in early development. In this review, we summarize the role of miR-21 in the molecular pathogenesis of DN and several therapeutic strategies to use miR-21 as a therapeutic target in DN. The existing experimental interventions offer a way to rectify the lower miRNA levels as well as to reduce the higher levels. Synthetic miRNAs also referred to as miR-mimics, can compensate for abnormally low miRNA levels. Furthermore, strategies like oligonucleotides can be used to alter the miRNA levels. It is reasonable to target miR-21 for improved results because it directly contributes to the pathological processes of kidney diseases, including DN.

Keywords: LNA-21; antagomirs; antisense oligonucleotides (ASOs); chronic kidney disease; diabetes; hsa-miR-21; miR-21-3p; miR-21-5p; nephropathy; pharmacological silencing of miR-21; small interfering RNAs (siRNAs).

Figure 1

Role of miR-21 in the pathogenesis of diabetic nephropathy. miR-21, microRNA-21; PTEN, phosphatase and TENsin homolog; TGF-β, transforming growth factor-β; TIMP3, tissue inhibitor of metalloproteinases 3; MCP-1, monocyte chemoattractant protein 1; CDC25A, cell division cycle 25A; CDK6, cyclin dependent kinase 6; NF-κB, nuclear factor κB; PDCD4, programmed cell death 4; IL-1β, interleukin-1β; TNF-α, tumor necrosis factor α [10,23].

Figure 2

Strategies to use miR-21 as a therapeutic target. Abbreviations: AS-IV: astragaloside IV; ASO: antisense oligonucleotide; LNA: locked nucleic acid.