TLR4/NF-κB Signaling Induces GSDMD-Related Pyroptosis in Tubular Cells in Diabetic Kidney Disease.

Youliang Wang,Shuguang Yuan,Zhong Qu,Lin Sun,Jun Li,Si Wen,Fuyou Liu,Chang Wang,Xuejing Zhu,Xuemei Liu,Hong Liu

doi:10.3389/fendo.2019.00603

Youliang Wang, Shuguang Yuan + Show 9 more

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https://doi.org/10.3389/fendo.2019.00603

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Abstract

Gasdermin D (GSDMD) has been proven to be a key protein in the activation of pyroptosis. Pyroptosis of renal tubular epithelial cells contributes to the progression of tubular injury in kidney diseases. However, it remains elusive whether and how GSDMD is involved in the regulation of diabetic kidney disease (DKD). In this study, we found that tubular injury is accompanied by the up-regulation of Toll-like receptor 4 (TLR4) and GSDMD in patients with diabetic kidney disease. In addition, we discovered that the expressions of cleaved Caspase-1, active N-terminal fragments of GSDMD (GSDMD-NT), IL-18, and the secretion of IL-1β also increased in the kidneys of db/db mice. These changes were partially ameliorated following intraperitoneal injection of TAK-242, an inhibitor of TLR4. Similar results were observed in human tubular cells (HK-2) subjected to high-glucose (HG) conditions and treated with TAK-242 or parthenolide (inhibitor of NF-κB) by Western blot, Enzyme-linked immunosorbent assay (ELISA), and flow cytometry. These results indicated that TLR4/NF-κB signaling could induce GSDMD-mediated pyroptosis in tubular cells in DKD.

Highlights

Tubular injury induced by high glucose has been taken into consideration to be an independent risk factor for the progression of diabetic kidney disease (DKD) [1, 2]
Our aim in this study is to explore the effect of the Toll-like receptor 4 (TLR4)/NFκB pathway on the pyroptosis of renal tubular epithelial cells in DKD, and to investigate the role of Gasdermin D (GSDMD) in this TLR4/NF-κBmediated pathway
Results showed that GSDMD expression was positively correlated with TLR4 expression (r = 0.988, P = 0.000), proteinuria (r = 0.423, P = 0.01), tubular interstitial fibrosis and tubular atrophy (IFTA) scores (r = 0.510, P = 0.007), and negatively correlated with eGFR (r = −0.388, P = 0.012)

Summary

Introduction

Tubular injury induced by high glucose has been taken into consideration to be an independent risk factor for the progression of diabetic kidney disease (DKD) [1, 2]. Pyroptosis is a programmed cell death mediated by the activation of caspase family, such as caspase-1, in the pathogenesis of disorders characterized by excessive cell death and inflammation. This form of cell death is accompanied by water influx, cellular swelling, osmotic lysis, activation of NLRP3 inflammasome, and the release of pro-inflammatory cytokines, such as IL-1β and IL-18 [3, 4]. Few studies have focused on the role of pyroptosis in tubular cells of diabetic kidney disease

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