Therapeutic potential for renal fibrosis by targeting Smad3-dependent noncoding RNAs

Abstract

Renal fibrosis is a characteristic hallmark of chronic kidney disease (CKD) that ultimately results in renal failure, leaving patients with few therapeutic options. TGF-β is a master regulator of renal fibrosis and mediates progressive renal fibrosis via both canonical and noncanonical signaling pathways. In the canonical Smad signaling, Smad3 is a key mediator in tissue fibrosis and mediates renal fibrosis via a number of noncoding RNAs (ncRNAs). In this regard, targeting Smad3-dependent ncRNAs may offer a specific therapy for renal fibrosis. This review highlights the significance and innovation of TGF-β/Smad3-associated ncRNAs as biomarkers and therapeutic targets in renal fibrogenesis. In addition, the underlying mechanisms of these ncRNAs and their future perspectives in the treatment of renal fibrosis are discussed.

Keywords: Smad3; TGF-β; noncoding RNAs; renal fibrosis; therapy.

Graphical abstract

Figure 1

Regulation of miRNAs in TGF-β/Smad3-mediated renal fibrosis After binding to its receptors, TGF-β1 activates Smad3 to induce fibrogenic miRNAs while suppressing antifibrotic miRNAs to regulate fibrosis, which is reversed by Smad7.

Figure 2

Regulation of lncRNAs in the TGF-β/Smad3-mediated renal fibrosis Smad3 is a key pathway in the development of CKD by inducing fibrogenic lncRNAs while inhibiting antifibrotic miRNAs.

Figure 3

RNA-based therapeutics in the treatment of renal fibrosis There are several RNA-based therapies for renal fibrosis, including (A) antisense oligonucleotides; (B) RNAi; (C) RNA aptamers; (D) ncRNAs; (E) CRISPR-Cas gene editing; (F) RNA nanoparticles.

Figure 4

Treatments for renal fibrosis by targeting Smad3 There are a number of therapeutic approaches for renal fibrosis, including a variety of Smad3 inhibitors, posttranslational modifications, and RNA-based therapeutics.