Downregulation of PDZK1 by TGF-ß1 promotes renal fibrosis via inducing epithelial-mesenchymal transition of renal tubular cells.
Biochem Pharmacol
; 220: 116015, 2024 Feb.
Article
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| MEDLINE
| ID: mdl-38158021
ABSTRACT
Transforming growth factor-beta 1 (TGF-ß1)-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-ß1-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-ß1 expression and the degree of renal fibrosis. In addition, TGF-ß1 downregulated the mRNA expression of PDZK1 in a time- and concentration-dependent manner in vitro. The downregulation of PDZK1 exacerbated TGF-ß1-induced EMT upon oxidative stress, while the overexpression of PDZK1 had the converse effect. Subsequent investigations demonstrated that TGF-ß1 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.
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MEDLINE
Asunto principal:
Insuficiencia Renal Crónica
/
Factor de Crecimiento Transformador beta1
Idioma:
En
Revista:
Biochem Pharmacol
Año:
2024
Tipo del documento:
Article