TGF-β/Smad Signaling Pathway in Tubulointerstitial Fibrosis

Abstract

Chronic kidney disease (CKD) was a major public health problem worldwide. Renal fibrosis, especially tubulointerstitial fibrosis, is final manifestation of CKD. Many studies have demonstrated that TGF-β/Smad signaling pathway plays a crucial role in renal fibrosis. Therefore, targeted inhibition of TGF-β/Smad signaling pathway can be used as a potential therapeutic measure for tubulointerstitial fibrosis. At present, a variety of targeting TGF-β1 and its downstream Smad proteins have attracted attention. Natural products used as potential therapeutic strategies for tubulointerstitial fibrosis have the characteristics of acting on multiple targets by multiple components and few side effects. With the continuous research and technique development, more and more molecular mechanisms of natural products have been revealed, and there are many natural products that inhibited tubulointerstitial fibrosis via TGF-β/Smad signaling pathway. This review summarized the role of TGF-β/Smad signaling pathway in tubulointerstitial fibrosis and natural products against tubulointerstitial fibrosis by targeting TGF-β/Smad signaling pathway. Additionally, many challenges and opportunities are presented for inhibiting renal fibrosis in the future.

Keywords: TGF-β/Smad signaling pathway; chronic kidney disease; natural products; renal fibrosis; tubulointerstitial fibrosis.

FIGURE 1

Canonical TGF-β/Smad pathway. TGF-β synthesized in precursor form combines with latency-associated peptide (LAP) that promotes attachment with LTBP through the formation of disulfide bonds, which is released from the LAP and LTBP and becomes active when exposed to various stimuli. The active TGF-β binds to TGFβRII, which recruits and activates TGFβRI through phosphorylated the GS domain in TGFβRI. TGFβRI phosphorylates and activates Smad2 and Smad3 (R-Smads). Smad4 combined with phosphorylated R-Smads to form a trimer complex for transcriptional regulation. Smad7 is involved and acts as a negative feedback regulation loop to regulate the target genes that regulate cell homeostasis.

FIGURE 2

TGF-β1/Smad3 signaling regulates lncRNAs in renal fibrosis. (1) Erbb4-IR promotes renal fibrosis by suppressing miR-29b and downregulating Smad7. (2) lncRNA9884 is significantly upregulated in renal fibrosis. (3) The increased lncRNA Arid2-IR leads to ECM production in renal fibrosis. (4) lncRNA-ATB activates TGF-β/Smad2/3 pathway, thus promoting inflammation, cell apoptosis and senescence.