TGF-Beta as a Master Regulator of Diabetic Nephropathy

Abstract

Diabetic nephropathy (DN) is one of the most common complications in diabetes mellitus and the leading cause of end-stage renal disease. TGF-β is a pleiotropic cytokine and has been recognized as a key mediator of DN. However, anti-TGF-β treatment for DN remains controversial due to the diverse role of TGF-β1 in DN. Thus, understanding the regulatory role and mechanisms of TGF-β in the pathogenesis of DN is the initial step towards the development of anti-TGF-β treatment for DN. In this review, we first discuss the diverse roles and signaling mechanisms of TGF-β in DN by focusing on the latent versus active TGF-β1, the TGF-β receptors, and the downstream individual Smad signaling molecules including Smad2, Smad3, Smad4, and Smad7. Then, we dissect the regulatory mechanisms of TGF-β/Smad signaling in the development of DN by emphasizing Smad-dependent non-coding RNAs including microRNAs and long-non-coding RNAs. Finally, the potential therapeutic strategies for DN by targeting TGF-β signaling with various therapeutic approaches are discussed.

Keywords: Smad; TGF-β signaling; diabetic nephropathy; fibrosis; inflammation.

Figure 1

The regulatory role of TGF-β signal in DN. TGF-β ligands (TGF-β1/2/3) transduce the transmembrane signal through binding to TGFBR2 and TGFBR1, resulting in the phosphorylation of downstream Smad2/3. Phosphorylated Smad2/3 form the complexes with Smad4 and translocate into the nucleus to regulate the transcription of target genes. Smad2/3 can also be activated by signal crosstalk with ERK/p38 MAPK pathway. Smad7, an inhibitory Smad, acts to inhibit Smad2/3 phosphorylation by targeting TGFBR1. In addition, Smad7 also induces IκBα, an NK-κB inhibitor, to suppress NF-κB signaling. TGF-β also induces many Smad3-dependent miRNAs/lnRNAs to regulate DN, among which miR-21, miR-192, miR-377, Erbb4-IR, and lncRNA9884 are upregulated and pathogenic. However, miR-29a/b, miR-200a, let-7b, and lnc-TSI are downregulated and renoprotective. The TGF-β signal-targeted inhibitors or agonists, whose efficacy for DN treatment has been validated in animal studies, are also labeled in the illustration. The line with an arrow end means positive regulation, while that with the blunt end means negative regulation or inhibition.