Redirecting TGF-β Signaling through the β-Catenin/Foxo Complex Prevents Kidney Fibrosis

Abstract

TGF- is a key profibrotic factor, but targeting TGF- to prevent fibrosis also abolishes its protective anti-inflammatory effects. Here, we investigated the hypothesis that we can redirect TGF- signaling by preventing downstream profibrotic interaction of -catenin with T cell factor (TCF), thereby enhancing the interaction of-catenin with Foxo, a transcription factor that controls differentiation of TGF- induced regulatory T cells (iTregs), and thus, enhance anti-inflammatory effects of TGF- In iTregs derived from EL4 T cells treated with recombinant human TGF-1 (rhTGF-1) , inhibition of-catenin/TCF transcription with ICG-001 increased Foxp3 expression, interaction of -catenin and Foxo1, binding of Foxo1 to the Foxp3 promoter, and Foxo transcriptional activity. Moreover, the level of-catenin expression positively correlated with the level of Foxo1 binding to the Foxp3 promoter and Foxo transcriptional activity. T cell fate mapping in Foxp3 Ly5.1/5.2 mice revealed that coadministration of rhTGF-1 and ICG-001 further enhanced the expansion of iTregs and natural Tregs observed with rhTGF-1 treatment alone. Coadministration of rhTGF-1 with ICG-001 also increased the number of Tregs and reduced inflammation and fibrosis in the kidney fibrosis models of unilateral ureteric obstruction and ischemia-reperfusion injury. Notably, ICG-001 prevented the fibrosis in distant organs (lung and liver) caused by rhTGF-1. Together, our results show that diversion of -catenin from TCF- to Foxo-mediated transcription inhibits the-catenin/TCF-mediated profibrotic effects of TGF- while enhancing the -catenin/Foxo-mediated anti-inflammatory effects. Targeting-catenin/Foxo may be a novel therapeutic strategy in the treatment of fibrotic diseases that lead to organ failure.

Effect of sitagliptin on tubulointerstitial Wnt/β‐catenin signalling in diabetic nephropathy

“…Joo et al confirmed that sitagliptin can restore Foxo3a activity and reduce renal structural and functional impairment by reducing the ratio of P‐Foxo3a/total Foxo3a in 5/6 nephrectomy rats. Further studies by Qiao et alconfirmed that ICG‐001's targeted blockage of β‐catenin/TCF signalling activation induced by TGF‐β1 can promote β‐catenin/Foxo binding, inhibit TGF‐β1‐induced renal fibrosis, and enhance the anti‐inflammatory activity of TGF‐β1. However, whether the sitagliptin‐mediated protective effect in the kidney via blocking high glucose‐induced Wnt/β‐catenin signalling is related to the enhanced Foxo activity resulting from the inhibition of β‐catenin‐induced TCF signalling requires further investigation.…”

Inflammation and Premature Ageing in Chronic Kidney Disease

“…Kidney-derived klotho is of particular interest as a potential treatment for inflammation and premature ageing in CKD, because klotho-deficient mice and patients with CKD have similar phenotypes, such as EVA and a pro-inflammatory status, and klotho is related to ageing in both humans and mice [70,72]. Similar to the NRF2 system, klotho is repressed in CKD, and stimulation of klotho can ameliorate oxidative stress and mitochondrial function [108], renal fibrosis [152], inflammation [72], as well as premature ageing [108], including EVA [55,[81][82][83][111][112][113].…”

Promotion of β-catenin/Foxo1 signaling ameliorates renal interstitial fibrosis

“…The contrasting effects of TGF-β (profibrotic versus anti-inflammatory) have posed a considerable challenge in the treatment of fibrotic diseases affecting the kidneys and other organs. However, we have recently described the role of β-catenin/Foxo in the redirection of TGF-β signaling from an undesirable profibrotic to a beneficial anti-inflammatory function [6].…”