Diverse Role of TGF-β in Kidney Disease

Abstract

Inflammation and fibrosis are two pathological features of chronic kidney disease (CKD). Transforming growth factor-β (TGF-β) has been long considered as a key mediator of renal fibrosis. In addition, TGF-β also acts as a potent anti-inflammatory cytokine that negatively regulates renal inflammation. Thus, blockade of TGF-β inhibits renal fibrosis while promoting inflammation, revealing a diverse role for TGF-β in CKD. It is now well documented that TGF-β1 activates its downstream signaling molecules such as Smad3 and Smad3-dependent non-coding RNAs to transcriptionally and differentially regulate renal inflammation and fibrosis, which is negatively regulated by Smad7. Therefore, treatments by rebalancing Smad3/Smad7 signaling or by specifically targeting Smad3-dependent non-coding RNAs that regulate renal fibrosis or inflammation could be a better therapeutic approach. In this review, the paradoxical functions and underlying mechanisms by which TGF-β1 regulates in renal inflammation and fibrosis are discussed and novel therapeutic strategies for kidney disease by targeting downstream TGF-β/Smad signaling and transcriptomes are highlighted.

Keywords: Smads; TGF-β; fibrosis; inflammation; mechanisms; therapy.

FIGURE 1

The canonical TGF-β/Smad signaling in fibrosis. Once released, active TGF-β1 binds TβRII and activates TβRI and R-Smads (Smad2 and Smad3), resulting in formation of a complex with Smad4. The Smad2/3/4 complex then translates into the nucleus and binds to the target genes to induce fibrosis and inflammation. TGF-β, transforming growth factor β; TβRI, TGF-β receptor type I; TβRII, TGF-β receptor type II.

FIGURE 2

The overview of crosstalk pathways associated with renal fibrosis and inflammation. Many stress molecules such as TGF-β1, EGF, TGF-α, ROS, AGEs, and Ang II can activate individual pathways and interact with TGF-β/Smad signaling pathway to regulate renal fibrosis and inflammation. Among TGF-β super family, the BMP signaling negatively regulates TGF-β/Smad signaling. In TGF-β/Smad signaling, Smad7 inhibits the phosphorylation of TβRI and R-Smads via ubiquitin degradation mechanism. Meanwhile, Smad7 also alleviates renal inflammatory by inducing IκBα, therefore inhibiting NF-κB-driven inflammation. AGEs, advanced glycation end products; RAGE, receptor for AGE; Ang II, angiotensin II; AT1/2, Ang II receptor 1 and 2; NF-κB, nuclear factor κ-light-chain-enhancer of activated B cells; EGF, epidermal growth factor; EGFR, EGF receptor; c-Src, proto-oncogene tyrosine-protein kinase Src; ROS, reactive oxygen species; BMP, bone morphogenic protein; ALK, activin receptor-like kinases; TNF-α, tumor necrosis factor α; TNFR, TNF receptor; IL-1, Interleukin 1; IL-1R, IL-1 receptor; Nox, NADPH oxidase.

FIGURE 3

TGF-β/Smad3-dependent miRNAs and lncRNAs related to renal fibrosis and inflammation. TGF-β/Smad3-dependent miRNAs and lncRNAs are classified as anti-fibrotic (powder blue), pro-fibrotic (sky blue), anti-inflammatory (lavender), and pro-inflammatory effect (plum). The integrated area indicates multiple functions for each miRNA/lncRNA.

FIGURE 4

Therapeutic potentials by targeting TGF-β signaling. Anti-TGF-β treatment by: (a) targeting upstream signaling; (b) rebalancing Smad3/Smad7 signaling; and (c) targeting Smad3-dependent miRNAs/lncRNAs.