Modulation of TGF-β signaling new approaches toward kidney disease and fibrosis therapy

Abstract

The prevalence of chronic kidney disease (CKD) is increasing worldwide, posing a significant healthcare challenge. Despite the immense burden of CKD, optimal therapies remain limited in impact. Kidney fibrosis is a common mediator of all CKD progression, characterized by excessive extracellular matrix deposition and scarring of kidney parenchyma. Transforming growth factor-β (TGF-β) is a potent pro-fibrotic cytokine that signals through canonical and non-canonical pathways to promote kidney cell damage and fibrosis progression, thus garnering much interest as an optimal therapeutic target for CKD. However, the clinical translation of TGF-β inhibition in CKD and other disease settings has faced substantial challenges, particularly due to the highly pleiotropic effects of TGF-β in organ homeostasis and disease. Here, we review the kidney cell-specific biological effects of TGF-β signaling, discuss the current challenges in therapeutic targeting TGF-β in CKD, and provide the rationale for alternative targeting strategies of TGF-β signaling as potential approaches in CKD therapy. Selective inhibition of TGF-β signaling modulators to fine-tune TGF-β inhibition without a broad blockade may lead to new and safer treatments for CKD.

Keywords: ALK1; ALK5; CKD; DKD; HIPK2; Kidney fibrosis; LRG1.; Smad3; TGF-β; TGFBR2.

Figure 1

TGF-β signaling. A. Schematics of Smad-mediated canonical and Smad-independent noncanonical TGF-β signaling transduction are shown. Cell type and stage-specific TGF-β signaling is dictated by the expression of extracellular and intracellular signaling mediators and inhibitors and the combination of transcriptional repressors and activators present. B. TGF-β signaling in endothelial cells involving the interplay between two type 1 TGF-β receptors (ALK1 vs. ALK5) is shown.

Figure 2

Regulation of TGF-β signaling modulators as an alternative therapeutic approach in CKD. A. Examples of current approaches in TGF-β signaling inhibitors are shown. B. Inhibitors of TGF-β signaling modulators are shown on the left as an approach to dampen the hyperactive TGF-β signaling in disease settings without a complete blockade.