The novel role of ER protein TXNDC5 in the pathogenesis of organ fibrosis: mechanistic insights and therapeutic implications

Abstract

Fibrosis-related disorders account for an enormous burden of disease-associated morbidity and mortality worldwide. Fibrosis is defined by excessive extracellular matrix deposition at fibrotic foci in the organ tissue following injury, resulting in abnormal architecture, impaired function and ultimately, organ failure. To date, there lacks effective pharmacological therapy to target fibrosis per se, highlighting the urgent need to identify novel drug targets against organ fibrosis. Recently, we have discovered the critical role of a fibroblasts-enriched endoplasmic reticulum protein disulfide isomerase (PDI), thioredoxin domain containing 5 (TXNDC5), in cardiac, pulmonary, renal and liver fibrosis, showing TXNDC5 is required for the activation of fibrogenic transforming growth factor-β signaling cascades depending on its catalytic activity as a PDI. Moreover, deletion of TXNDC5 in fibroblasts ameliorates organ fibrosis and preserves organ function by inhibiting myofibroblasts activation, proliferation and extracellular matrix production. In this review, we detailed the molecular and cellular mechanisms by which TXNDC5 promotes fibrogenesis in various tissue types and summarized potential therapeutic strategies targeting TXNDC5 to treat organ fibrosis.

Genetic Association and Transferability for Urinary Albumin-Creatinine Ratio as a Marker of Kidney Disease in four Sub-Saharan African Populations and non-continental Individuals of African Ancestry

“…Genes from the BMP gene family play diverse roles in embryonic kidney development, regulating essential aspects of both ureteric bud and nephron development (Oxburgh et al, 2011). eQTLs around lead SNPs show potential interaction with TXNDC5 , a gene that promotes renal fibrosis by promoting TGF-β signalling in kidney fibroblasts (Chen et al, 2021; Hung et al, 2022). Variability of kidney function, confounding factors and allele frequency differences between datasets may explain why the rs9505286 signal was not replicated in Meta ALL or Meta NONRES (Marigorta et al, 2018).…”

Transcriptomic analysis of TGFβ-mediated fibrosis in primary human Tenon’s fibroblasts

“…Growth factors and reactive oxidants are released from damaged cells and trigger the activation and proliferation of fibroblasts 11 . CTGF is one such growth factor that has been found to play an important role in TGFβ-dependent myofibroblast differentiation and ECM production, indicated by its upregulated expression being highly enriched in the TGFβ-pathway (Figure 8d).…”

Transcriptomic analysis of TGFβ-mediated fibrosis in primary human Tenon’s fibroblasts

“…NOX4-dependent generation of hydrogen peroxide is a requirement for TGFβ induced myo broblast differentiation, as well as ECM production 14 . TXNDC5 facilitates proper protein folding in the endoplasmic reticulum and mediates redox reactions via interacting with NADPH oxidase 11 . These genes promote conjunctival brosis by activation of SMAD3-dependent TGFβ-signaling and lead to differentiation of HSCs into myo broblasts, this results in considerable myo broblast proliferation and ECM production 11 .…”

“…TXNDC5 facilitates proper protein folding in the endoplasmic reticulum and mediates redox reactions via interacting with NADPH oxidase 11 . These genes promote conjunctival brosis by activation of SMAD3-dependent TGFβ-signaling and lead to differentiation of HSCs into myo broblasts, this results in considerable myo broblast proliferation and ECM production 11 . Notably, we observed the downregulated expression of SOD3 in our TGFβ treated samples.…”