Activation of ERK accelerates repair of renal tubular epithelial cells, whereas it inhibits progression of fibrosis following ischemia/reperfusion injury.

Abstract

Extracellular signal-regulated kinase (ERK) signals play important roles in cell death and survival. However, the role of ERK in the repair process after injury remains to be defined in the kidney. Here, we investigated the role of ERK in proliferation and differentiation of tubular epithelial cells, and proliferation of interstitial cells following ischemia/reperfusion (I/R) injury in the mouse kidney. Mice were subjected to 30min of renal ischemia. Some mice were administered with U0126, a specific upstream inhibitor of ERK, daily during the recovery phase, beginning at 1day after ischemia until sacrifice. I/R caused severe tubular cell damage and functional loss in the kidney. Nine days after ischemia, the kidney was restored functionally with a partial restoration of damaged tubules and expansion of fibrotic lesions. ERK was activated by I/R and the activated ERK was sustained for 9days. U0126 inhibited the proliferation, basolateral relocalization of Na,K-ATPase and lengthening of primary cilia in tubular epithelial cells, whereas it enhanced the proliferation of interstitial cells and accumulation of extracellular matrix. Furthermore, U0126 elevated the expression of cell cycle arrest-related proteins, p21 and phospholylated-chk2 in the post-ischemic kidney. U0126 mitigated the post-I/R increase of Sec10 which is a crucial component of exocyst complex and an important factor in ciliogenesis and tubulogenesis. U0126 also enhanced the expression of fibrosis-related proteins, TGF-β1 and phosphorylated NF-κB after ischemia. Our findings demonstrate that activation of ERK is required for both the restoration of damaged tubular epithelial cells and the inhibition of fibrosis progression following injury.

• Authors: Hee-Seong Jang, Sang Jun Han, Jee In Kim, Sanggyu Lee, Joshua H Lipschutz, Kwon Moo Park
• Journal: Biochimica et biophysica acta (Biochim Biophys Acta) Vol. 1832 Issue 12 Pg. 1998-2008 (Dec 2013) ISSN: 0006-3002 [Print] Netherlands
• PMID: 23851027 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2013.

Chemical References

• Butadienes
• Enzyme Inhibitors
• NF-kappa B
• Nitriles
• Reactive Oxygen Species
• Transforming Growth Factor beta1
• U 0126
• Creatinine
• Extracellular Signal-Regulated MAP Kinases
• MAP Kinase Kinase 1

Topics

• Animals
• Blotting, Western
• Butadienes (pharmacology)
• Cilia (metabolism, pathology)
• Creatinine (blood)
• Enzyme Activation
• Enzyme Inhibitors (pharmacology)
• Epithelial Cells (cytology, metabolism)
• Extracellular Matrix (metabolism)
• Extracellular Signal-Regulated MAP Kinases (metabolism)
• Fibrosis (etiology, metabolism, prevention & control)
• Fluorescent Antibody Technique
• Immunoenzyme Techniques
• Kidney Tubules (cytology, metabolism)
• MAP Kinase Kinase 1 (antagonists & inhibitors, metabolism)
• Male
• Mice
• Mice, Inbred C57BL
• NF-kappa B (metabolism)
• Nitriles (pharmacology)
• Phosphorylation
• Reactive Oxygen Species (metabolism)
• Reperfusion Injury (complications, metabolism, pathology)
• Signal Transduction
• Transforming Growth Factor beta1 (metabolism)