The Ser/Thr kinase p90RSK promotes kidney fibrosis by modulating fibroblast-epithelial crosstalk

Ling Lin, Chaowen Shi, Zhaorui Sun, Nhat Tu Le, Jun Ichi Abe, Kebin Hu

Research output: Contribution to journalArticle

Abstract

Healthy kidney structure and environment rely on epithelial integrity and interactions between epithelial cells and other kidney cells. The Ser/Thr kinase 90 kDa ribosomal protein S6 kinase 1 (p90RSK) belongs to a protein family that regulates many cellular processes, including cell motility and survival. p90RSK is predominantly expressed in the kidney, but its possible role in chronic kidney disease (CKD) remains largely unknown. Here, we found that p90RSK expression is dramatically activated in a classic mouse obstructive chronic kidney disease model, largely in the interstitial FSP-1-positive fibroblasts. We generated FSP-1-specific p90RSK transgenic mouse (RSKTg) and discovered that these mice, after obstructive injury, display significantly increased fibrosis and enhanced tubular epithelial damage compared with their wt littermates (RSK-wt), indicating a role of p90RSK in fibroblast-epithelial communication. We established an in vitro fibroblast-epithelial coculture system with primary kidney fibroblasts from RSK-Tg and RSK-wt mice and found that RSK-Tg fibroblasts consistently produce excessive H2O2 causing epithelial oxidative stress and inducing nuclear translocation of the signaling protein β-catenin. Epithelial accumulation of β-catenin, in turn, promoted epithelial apoptosis by activating the transcription factor forkhead box class O1 (FOXO1). Of note, blockade of reactive oxygen species (ROS) or β-catenin or FOXO1 activity abolished fibroblast p90RSK-mediated epithelial apoptosis. These results make it clear that p90RSK promotes kidney fibrosis by inducing fibroblast-mediated epithelial apoptosis through ROS-mediated activation of β-catenin/FOXO1 signaling pathway.

Original languageEnglish (US)
Pages (from-to)9901-9910
Number of pages10
JournalJournal of Biological Chemistry
Volume294
Issue number25
DOIs
StatePublished - Jan 1 2019

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Fibroblasts
Crosstalk
Fibrosis
Phosphotransferases
Catenins
Kidney
Apoptosis
Chronic Renal Insufficiency
Reactive Oxygen Species
90-kDa Ribosomal Protein S6 Kinases
Activating Transcription Factors
Oxidative stress
Protein Transport
Coculture Techniques
Transgenic Mice
Cell Movement
Cell Survival
Oxidative Stress
Epithelial Cells
Chemical activation

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Lin, Ling ; Shi, Chaowen ; Sun, Zhaorui ; Le, Nhat Tu ; Abe, Jun Ichi ; Hu, Kebin. / The Ser/Thr kinase p90RSK promotes kidney fibrosis by modulating fibroblast-epithelial crosstalk. In: Journal of Biological Chemistry. 2019 ; Vol. 294, No. 25. pp. 9901-9910.
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The Ser/Thr kinase p90RSK promotes kidney fibrosis by modulating fibroblast-epithelial crosstalk. / Lin, Ling; Shi, Chaowen; Sun, Zhaorui; Le, Nhat Tu; Abe, Jun Ichi; Hu, Kebin.

In: Journal of Biological Chemistry, Vol. 294, No. 25, 01.01.2019, p. 9901-9910.

Research output: Contribution to journalArticle

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