Targeting TGF-β Signaling in Kidney Fibrosis

Abstract

Renal fibrosis is the final common pathway of numerous progressive kidney diseases, and transforming growth factor-β (TGF-β) has an important role in tissue fibrosis by up-regulating matrix protein synthesis, inhibiting matrix degradation, and altering cell-cell interaction. Many strategies targeting TGF-β, including inhibition of production, activation, binding to the receptor, and intracellular signaling, have been developed. Some of them were examined in clinical studies against kidney fibrosis, and some are applied to other fibrotic diseases or cancer. Here, I review the approaches targeting TGF-β signaling in kidney fibrosis.

Keywords: antisense; galunisertib; gene therapy; glomerulosclerosis; interstitial fibrosis; ligand trap; pirfenidone; siRNA.

Figure 1

Schematic overview of the strategies targeting TGF-β signaling. The first step is the inhibition of production of TGF-β at the transcription and translation level. Transcription or translation of TGF-β mRNA can be blocked by pirfenidone, antisense oligodeoxynucleotides (ODN) (Trabedersen), siRNA, or DNA enzymes. In this step, we should develop a vehicle to carry the drug to the inside of the specific cells. The second step is inhibitory strategies targeting the activation of TGF-β, and its binding to the receptor. Integrin αvβ6 activates TGF-β, and anti-αvβ6 antibody (STX-100) is expected to suppress kidney fibrosis by antagonizing the activation of TGF-β. A ligand trap to block the binding of active TGF-β to its receptor was clinically examined by using the antibody for TGF-β (LY2382770, fresolimumab). Decorin or TGFβRII/Fc was reported to competitively suppress TGF-β-induced fibrosis in an animal model. The third step is the blockade of intracellular signaling following the activation of the TGF-β receptor. Galunisertib is an oral inhibitor of TGF-β type I receptor kinase, and down-regulates the phosphorylation of SMAD2/3. SMAD6/7 can inhibit the phosphorylation of SMAD2/3, and thereby block TGF-β signaling. Additionally, SMAD7 degrades type I TGF-β receptor in combination with Smurf1/2. BT173, an inhibitor of homeo-domain interacting protein kinase 2 (HIPK2), which binds to HIPK2 and reduces the interaction between HIPK2 and SMAD4, thereby inhibiting the subsequent SMAD3 phosphorylation and activation. 22-oxacalcitriol (OCT) binds to the vitamin D receptor (VDR), forming a PPM1A/VDR/OCT complex, which dephosphorylates SMAD3, terminating TGF-β-SMAD3 signaling. BMP-SMAD1/5/8 signaling antagonize TGF-β-SMAD3 signaling by inducing SMAD6/7. (Grey arrow means promotion, and T bar means inhibitory effect.).