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Antagonistic Effect of Jiawei Shengjiang San on a Rat Model of Diabetic Nephropathy: Related to EGFR/MAPK3/1 Signaling Pathway
Published on: May 10, 2024
Genetic or pharmacologic blockade of EGFR inhibits renal fibrosis
Na Liu1, Jian-Kan Guo, Maoyin Pang
1Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine, China.
Abstract:
Although enhanced activation of the EGF receptor (EGFR) associates with the development and progression of renal fibrosis, the mechanisms linking these observations are not completely understood. Here, after unilateral ureteral obstruction (UUO), wild-type mice exhibited sustained EGFR phosphorylation in the kidney and developed renal fibrosis that was more severe than the renal fibrosis observed in waved-2 mice, which have reduced EGFR tyrosine kinase activity. Waved-2 mice also showed fewer renal tubular cells arrested at G2/M, reduced expression of α-smooth muscle actin (α-SMA), downregulation of multiple genes encoding profibrogenic cytokines, including TGF-β1, and dephosphorylation of Smad3, STAT3, and ERK1/2. Administration of the specific EGFR inhibitor gefitinib recapitulated this phenotype in wild-type mice after UUO. Furthermore, inactivation of either EGFR or STAT3 reduced UUO-induced expression of lipocalin-2, a molecule associated with the pathogenesis of CKD. In cultured renal interstitial fibroblasts, inhibition of EGFR also abrogated TGF-β1- or serum-induced phosphorylation of EGFR, STAT3, ERK1/2, and Smad3 as well as expression of α-SMA and extracelluar matrix proteins. Taken together, these data suggest that EGFR may mediate renal fibrogenesis by promoting transition of renal epithelial cells to a profibrotic phenotype, increased production of inflammatory factors, and activation of renal interstitial fibroblasts. Inhibition of EGFR may have therapeutic potential for fibrotic kidney disease.
Insights
Enhanced epidermal growth factor receptor (EGFR) activation drives renal fibrosis by promoting profibrotic phenotypes and fibroblast activation. EGFR inhibition shows therapeutic potential for fibrotic kidney disease.
Area of Science:
- Nephrology
- Molecular Biology
- Cell Biology
Background:
- Enhanced epidermal growth factor receptor (EGFR) activation is linked to renal fibrosis development and progression.
- The precise mechanisms connecting EGFR signaling to renal fibrogenesis remain incompletely understood.
Purpose of the Study:
- To investigate the role of EGFR in mediating renal fibrosis following unilateral ureteral obstruction (UUO).
- To elucidate the downstream signaling pathways affected by EGFR activation in renal fibrosis.
- To evaluate the therapeutic potential of EGFR inhibition in a mouse model of kidney fibrosis.
Main Methods:
- Utilized a unilateral ureteral obstruction (UUO) mouse model comparing wild-type and waved-2 mice with reduced EGFR activity.
- Administered gefitinib, a specific EGFR inhibitor, to wild-type mice post-UUO.
- Analyzed renal tubular cell cycle arrest, α-smooth muscle actin (α-SMA) expression, profibrogenic cytokine gene expression, and phosphorylation of Smad3, STAT3, and ERK1/2.
- Assessed the impact of EGFR or STAT3 inactivation on lipocalin-2 expression.
- Investigated EGFR signaling in cultured renal interstitial fibroblasts.
Main Results:
- Wild-type mice showed more severe renal fibrosis, sustained EGFR phosphorylation, increased G2/M cell arrest, elevated α-SMA, and upregulated profibrogenic factors compared to waved-2 mice after UUO.
- Gefitinib treatment in wild-type mice mimicked the protective phenotype observed in waved-2 mice.
- EGFR or STAT3 inactivation reduced UUO-induced lipocalin-2 expression.
- EGFR inhibition in fibroblasts abrogated TGF-β1- or serum-induced signaling pathways and matrix protein production.
Conclusions:
- EGFR signaling plays a critical role in mediating renal fibrogenesis through epithelial cell transition to a profibrotic phenotype, inflammation, and fibroblast activation.
- EGFR inhibition demonstrates significant therapeutic potential for treating fibrotic kidney disease.
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