TGF-β signaling in diabetic nephropathy: An update

Abstract Diabetic nephropathy (DN) is a common complication in patients with diabetes and the leading cause of end-stage renal disease. Accumulating evidence shows that transforming growth factor beta-1 (TGF-β1) is a key mediator in the pathogenesis of DN. TGF-β1 binds to its receptors to activate canonical and noncanonical downstream signaling pathways to exert its biological activities. Among them, canonical Smad signaling is the major pathway responsible for the development of DN. In addition to TGF-β1, many stress molecules, such as advanced glycation end products (AGEs), angiotensin II (Ang II), and C-reactive protein (CRP), can also activate Mothers against decapentaplegic homologs (Smads) via the extracellular signal-regulated kinase (ERK)/p38 mitogen-activated protein kinase (MAPK) cross talk mechanism. Furthermore, TGF-β/Smad signaling can also cross talk with nuclear factor kappa B (NF-κB) signaling to regulate renal inflammation via the induction of IκBα by Smad7. In the context of renal fibrosis, Smad3 is pathogenic, while Smad2 and Smad7 are protective. TGF-β signaling also upregulates the pathogenic microRNAs (miRNAs) (namely, miR-21, miR-192, and miR-377) and long noncoding RNAs (lncRNAs) (namely, Erbb4-IR (intron region, IR), LncRNA9884, and Arid2-IR) but downregulates the protective miRNAs (namely, miR-29a/b and miR-200a) to mediate DN. Thus, targeting TGF-β signaling, either by blocking its ligand, its receptor (i.e., TGF-β receptor-2 [TGFBR2]), Smad3, and downstream miRNAs/lncRNAs or by overexpressing Smad7, has been shown to improve DN. In addition, pharmaceutically targeting TGF-β signaling using chemical inhibitors and traditional Chinese medicine (TCM), including Tangshen formula, Chaihuang-Yishen granule, and herbal extracts (berberine, asiatic acid, and naringenin), also shows renoprotective effect in diabetes. In summary, TGF-β signaling is a critical pathway leading to DN and may be a therapeutic target for combating DN.