Downregulation of PDZK1 by TGF-β1 promotes renal fibrosis via inducing epithelial-mesenchymal transition of renal tubular cells

  • Biochem Pharmacol. 2023 Dec 27:116015. doi: 10.1016/j.bcp.2023.116015.
Shuanghui Lu  1 ,  Xiu Chen  2 ,  Yujia Chen  2 ,  Yingqiong Zhang  2 ,  Jun Luo  2 ,  Huidi Jiang  3 ,  Luo Fang  4 ,  Hui Zhou  5
Affiliations
  • 1. Department of Pharmacy, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou 310022, China; College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
  • 2. College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
  • 3. College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China; Jinhua Institute of Zhejiang University, Jinhua 321036, China.
  • 4. Department of Pharmacy, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou 310022, China. Electronic address: [email protected].
  • 5. College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China; Jinhua Institute of Zhejiang University, Jinhua 321036, China. Electronic address: [email protected].
PMID: 38158021 DOI: 10.1016/j.bcp.2023.116015
Abstract

Transforming growth factor-beta 1 (TGF-β1)-induced epithelial-mesenchymal transition (EMT) of renal tubular cells promotes renal fibrosis and the progression of chronic kidney disease (CKD). PDZ domain-containing 1 (PDZK1) is highly expressed in renal tubular epithelial cells; however, its role in TGF-β1-induced EMT remains poorly understood. The present study showed that PDZK1 expression was extremely downregulated in fibrotic mouse kidneys and its negative correlation with TGF-β1 expression and the degree of renal fibrosis. In addition, TGF-β1 downregulated the mRNA expression of PDZK1 in a time- and concentration-dependent manner in vitro. The downregulation of PDZK1 exacerbated TGF-β1-induced EMT upon oxidative stress, while the overexpression of PDZK1 had the converse effect. Subsequent investigations demonstrated that TGF-β1 downregulated PDZK1 expression via p38 MAPK or PI3K/Akt signaling in vitro, but independently of ERK/JNK MAPK signaling. Meanwhile, inhibition of the p38/JNK MAPK or PI3K/Akt signaling using chemical inhibitors restored the PDZK1 expression, mitigated renal fibrosis, and elevated renal levels of endogenous Antioxidants carnitine and ergothioneine in adenine-induced CKD mice. These findings provide the first evidence suggesting a negative correlation between PDZK1 and renal fibrosis, and identifying PDZK1 as a novel suppressor of renal fibrosis in CKD through ameliorating oxidant stress.

Keywords
Epithelial to mesenchymal transition; Oxidative stress; PDZ domain-containing 1; Transforming growth factor-beta 1; p38 MAPK and PI3K/AKT signaling pathways.
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