Therapeutic potential of microRNAs for the treatment of renal fibrosis and CKD

Abstract

Chronic kidney disease (CKD), defined as reduced glomerular filtration rate, is increasingly becoming a major public health issue. At the histological level, renal fibrosis is the final common pathway leading to end-stage renal disease, irrespective of the initial injury. According to this view, antifibrotic agents should slow or halt the progression of CKD. However, due to multiple overlapping pathways stimulating fibrosis, it has been difficult to develop antifibrotic drugs that delay or reverse the progression of CKD. MicroRNAs (miRNAs) are small noncoding RNA molecules, 18-22 nucleotides in length, that control many developmental and cellular processes as posttranscriptional regulators of gene expression. Emerging evidence suggests that miRNAs targeted against genes involved in renal fibrosis might be potential candidates for the development of antifibrotic therapies for CKD. This review will discuss some of the miRNAs, such as Let-7, miR-21,-29, -192, -200,-324, -132, -212, -30, -126, -433, -214, and -199a, that are implicated in renal fibrosis and the potential to exploit these molecular targets for the treatment of CKD.

Keywords: chronic kidney disease; microRNA; renal fibrosis.

Fig. 1.

Renal pro- and antifibrotic micro (mi)RNAs for tubular epithelial cells (TECs), mesangial cells (MCs), and podocytes.

Fig. 2.

Key pro- and antifibrotic miRNAs implicated in transforming growth factor (TGF)-β signaling in the kidney. TGF-β is the central player in the initiation and progression of renal fibrosis by driving endothelial-to-mesangial transition (EndMT) and epithelial-to-mesenchymal transition (EMT), as well as extracellular matrix (ECM) remodeling and protein accumulation. Both canonical (Smad-dependent) and noncanonical (MAPKs and AKT) signaling pathways are involved and targeted by various miRNAs (boldface) that broadly favor or oppose fibrosis; however, given their broad range of gene targets, it is unlikely that a particular miRNA is strictly anti- or profibrotic. Plus, the same gene target may have conflicting actions. Although Zeb is implicated in the EMT program via in part the repression of E-cadherin, Zeb is also involved in repressing TGF-β expression. Conflicting actions are also reported for the ERK signaling cascade, which is involved in EndMT/EMT but also inhibits receptor Smads. In the text box, the human gene is shown where validated in human or in both human and rodent. Antifibrotic miRNAs are colored red; profibrotic miRNAs are colored green. See the text for additional details.

Fig. 3.

Delivery strategies for intrarenal targeting of miRNAs involving direct renal interstitial infusion, pelvic perfusion, and systemic delivery. (Kidney image adapted and reproduced with permission from the copyright holder http://servier.com).