Transforming growth factor‐β signalling in renal fibrosis: from Smads to non‐coding RNAs

Abstract

Transforming growth factor-β (TGF-β) is the key player in tissue fibrosis. However, antifibrotic therapy targeting this multifunctional protein may interfere with other physiological processes to cause side effects. Thus, precise therapeutic targets need to be identified by further understanding the underlying mechanisms of TGF-β1 signalling during fibrogenesis. Equilibrium of Smad signalling is crucial for TGF-β-mediated renal fibrosis, where Smad3 is pathogenic but Smad2 and Smad7 are protective. The activation of TGF-β1/Smad signalling triggers extracellular matrix deposition, and local myofibroblast generation and activation. Mechanistic studies have shown that TGF-β/Smad3 transits the microRNA profile from antifibrotic to profibrotic and therefore promotes renal fibrosis via regulating non-coding RNAs at transcriptional levels. More importantly, disease-specific Smad3-dependent long non-coding RNAs have been recently uncovered from mouse kidney disease models and may represent novel precision therapeutic targets for chronic kidney disease. In this review, mechanisms of TGF-β-driven renal fibrosis via non-coding RNAs and their translational capacities will be discussed in detail.

Diverse Role of TGF-β in Kidney Disease

“…These miRNAs regulate a wide range of biological processes, including fibrosis and inflammation. Increasing evidence has demonstrated that TGF-β1/Smad3 signaling regulates various miRNAs during the renal pathological processes (Meng et al, 2016;Tang et al, 2018). As a transcriptional factor, Smad3 can bind and upregulate or downregulate miRNAs to promote renal inflammation and fibrosis.…”

“…Moreover, miR-93, miR-216a, miR-217, miR-377, miR-382, miR-491-5p, miR-433 and miR-17-5p are also demonstrated to be TGF-β1/Smad3-regulated profibrotic miRNAs (Chung and Lan, 2015), whereas miR-let-7, miR-15b, miR-101, and miR-130b exert their antifibrotic effects by inhibiting the expression and activity of TβRI, thus limiting transduction of downstream TGF-β-mediated signals Tang et al, 2018). Other miRNAs such as miR-19b, miR-26a, miR-29, and miR-30 inhibit the TGF-β1/Smad signaling by targeting Smads or fibrotic transcriptional factors .…”

From expression footprints to causal pathways: contextualizing large signaling networks with CARNIVAL

“…TGF-β signaling is a main driver of fibrosis (33) . CARNIVAL's IgAN network captured all members of the TGF-β/RhoA pathway as up-regulated and linked through the biologically expected interactions.…”

“…The most significantly dysregulated pathways were identified by median p-value over different node penalties ( Figure 5). Among these, known drivers of renal fibrosis including TGF-β, WNT, and EGFR/ERbB signaling stand out (33)(34)(35) . These processes are significantly over-represented in CARNIVAL, but are not significant in GSEA (results not shown).…”

Interleukin-22 attenuates renal tubular cells inflammation and fibrosis induced by TGF-β1 through Notch1 signaling pathway

“…As TGF-b1/Smad3 has been considered as a major pathway for renal fibrogenesis [29], we detected protein expressions of Smad3 and phospho-Smad3. Result showed Smad3 phosphorylation increased following TGF-b1 treatment compared with untreated control (p < .01).…”