2. Academic Validation
  3. Empagliflozin, a sodium glucose cotransporter-2 inhibitor, ameliorates peritoneal fibrosis via suppressing TGF-β/Smad signaling

Empagliflozin, a sodium glucose cotransporter-2 inhibitor, ameliorates peritoneal fibrosis via suppressing TGF-β/Smad signaling

  • Int Immunopharmacol. 2021 Apr:93:107374. doi: 10.1016/j.intimp.2021.107374.
Yangping Shentu 1,  Yuyang Li 2,  Shicheng Xie 2,  Huanchang Jiang 2,  Shicheng Sun 2,  Rixu Lin 1,  Chaosheng Chen 3,  Yongheng Bai 4,  Yu Zhang 5,  Chenfei Zheng 6,  Ying Zhou 7
Affiliations

Affiliations

  • 1 Department of Pathology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China.
  • 2 The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China.
  • 3 Department of Nephrology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China.
  • 4 Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China; Institute of Kidney Health, Center for Health Assessment, Wenzhou Medical University, Wenzhou, Zhejiang 325000, China.
  • 5 Department of Hematology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China.
  • 6 Department of Nephrology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China. Electronic address: [email protected].
  • 7 Department of Nephrology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China. Electronic address: [email protected].
PMID: 33517222 DOI: 10.1016/j.intimp.2021.107374
Abstract

Sodium glucose cotransporter-2 (SGLT-2) inhibitor has been reported to exert a glucose-lowering effect in the peritoneum exposed to peritoneal dialysis solution. However, whether SGLT-2 inhibitors can regulate peritoneal fibrosis by suppressing TGF-β/Smad signaling is unclear. We aimed to (i) examine the effect of the SGLT-2 inhibitor empagliflozin in reducing inflammatory reaction and preventing peritoneal dialysis solution-induced peritoneal fibrosis and (ii) elucidate the underlying mechanisms. High-glucose peritoneal dialysis solution or transforming growth factor β1 (TGF-β1) was used to induce peritoneal fibrosis in vivo, in a mouse peritoneal dialysis model (C57BL/6 mice) and in human peritoneal mesothelial cells in vitro, to stimulate extracellular matrix accumulation. The effects of empagliflozin and adeno-associated virus-RNAi, which is used to suppress SGLT-2 activity, on peritoneal fibrosis and extracellular matrix were evaluated. The mice that received chronic peritoneal dialysis solution infusions showed typical features of peritoneal fibrosis, including markedly increased peritoneal thickness, excessive matrix deposition, increased peritoneal permeability, and upregulated α-smooth muscle actin and Collagen I expression. Empagliflozin treatment or downregulation of SGLT-2 expression significantly ameliorated these pathological changes. Inflammatory cytokines (TNF-α, IL-1β, IL-6) and TGF-β/Smad signaling-associated proteins, such as TGF-β1 and phosphorylated Smad (p-Smad3), decreased in the empagliflozin-treated and SGLT-2 downregulated groups. In addition, empagliflozin treatment and downregulation of SGLT-2 expression reduced the levels of inflammatory cytokines (TNF-α, IL-1β, IL-6), TGF-β1, α-smooth muscle actin, Collagen I, and p-Smad3 accumulation in human peritoneal mesothelial cells. Collectively, these results indicated that empagliflozin exerted a clear protective effect on high-glucose peritoneal dialysis-induced peritoneal fibrosis via suppressing TGF-β/Smad signaling.

Keywords

Empagliflozin; Peritoneal dialysis; Peritoneal fibrosis; Sodium glucose transporter-2.

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