Dact1, a Wnt-Pathway Inhibitor, Mediates Human Mesangial Cell TGF-ß1-Induced Apoptosis.

Chronic kidney disease (CKD) is a worldwide public health problem that affects millions of men and women of all ages and racial groups. Loss of mesangial cells (MC) represents an early common feature in the pathogenesis of CKD. Transforming growth factor-ß1 (TGF-ß1) is a key inducer of kidney damage and triggers several pathological changes in renal cells, notably MC apoptosis. However, the mechanism of MC apoptosis induced by TGF-ß1 remains elusive. Here, we demonstrate for the first time a novel regulatory pathway in which the disheveled-binding antagonist of ß-catenin 1 (Dact1) gene is upregulated by TGF-ß1, inducing MC apoptosis. We also show that the inhibitory effect of Dact1 and TGF-ß1 on the transcriptional activation of the pro-survival Wnt pathway is the mechanism of death induction. In addition, Dact1 mRNA/protein levels are increased in kidney remnants from 5/6 nephrectomized rats and strongly correlate with TGF-ß1 expression. Together, our results point to Dact1 as a novel element controlling MC survival that is causally related to CKD progression. J. Cell. Physiol. 232: 2104-2111, 2017. © 2016 Wiley Periodicals, Inc.

Transforming growth factor type beta (TGF-ß) requires reactive oxygen species to induce skeletal muscle atrophy.

Transforming growth factor beta 1 (TGF-ß1) is a classical modulator of skeletal muscle and regulates several processes, such as myogenesis, regeneration, and muscle function in skeletal muscle diseases. Skeletal muscle atrophy, characterised by the loss of muscle strength and mass, is one of the pathological conditions regulated by TGF-ß. Atrophy also results in increased myosin heavy chain (MHC) degradation and the expression of two muscle-specific E3 ubiquitin ligases, atrogin-1 and MuRF-1. Reactive oxygen species (ROS) are modulators of muscle wasting, and NAD(P)H oxidase (NOX) is one of the main sources of ROS. While it was recently found that TGF-ß1 induces atrophy in skeletal muscle, the underlying mechanism is not fully understood. In this study, the role of NOX-derived ROS in skeletal muscle atrophy induced by TGF-ß was assessed. TGF-ß1 induced an atrophic effect in C2C12 myotubes, as evidenced by decreased myotube diameter and MHC levels, together with increased MuRF-1 levels. Concomitantly, TGF-ß increased NOX-induced ROS contents. Interestingly, NOX inhibition through apocynin and the antioxidant treatment with N-acetyl cysteine (NAC) decreased increased ROS levels in myotubes. Additionally, both apocynin and NAC completely prevented the decreased MHC, decreased myotube diameter, and increased MuRF-1 induced by TGF-ß. Injection of TGF-ß1 into the tibialis anterior muscle induced atrophy, as observed by decreased fibre diameter and MHC levels, together with increased MuRF-1 levels. Likewise, TGF-ß increased the ROS contents in the smaller fibres of skeletal muscle. Additionally, the administration of NAC to mice prevented all atrophic effects and the increase in ROS induced by TGF-ß in the tibialis anterior. This is the first study to report that TGF-ß has an atrophic effect dependent on NOX-induced ROS in skeletal muscle.

Transforming growth factor-ß1 may be a key mediator of the fibrogenic properties of neural cells in leprosy.

Fibrosis is the main cause of irreversible nerve damage in leprosy. Phenotypic changes in Mycobacterium leprae (ML)-infected Schwann cells (SCs) have been suggested to mediate this process. We found that SC line cultures stimulated with ML upregulated transforming growth factor-ß1 (TGF-ß1), and that TGF-ß1 or ML induced increased numbers of α-smooth muscle actin (α-SMA)-positive cells with characteristic stress fibers. Mycobacterium leprae and TGF-ß1 also induced increased type I collagen and fibronectin mRNA and secretion and augmented mRNA levels of SOX9 and ZEB1, which are involved in the epithelial-mesenchymal transition. These effects could be inhibited by the TGF-ß1 type I receptor (ALK5) inhibitor, SB-431542. In nerve biopsies from leprosy-infected patients with varying grades of fibrosis (n = 11), type I and III collagen and fibronectin were found in the endoneurium and perineurium, α-SMA-positive cells filled the fibrotic perineurium but not the endoneurium, and CD34-positive fibroblasts predominated in the endoneurium. Results of transcriptional studies of 3 leprosy nerves and 5 controls were consistent with these data, but α-SMA and other mRNA levels were not different from those in the control samples. Our findings suggest that TGF-ß1 may orchestrate events, including reprogramming of the SC phenotype, leading to transdifferentiation, connective tissue cell expansion, and fibrogenesis in the evolution of leprosy nerve lesions during some evolutionary stages.