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Renoprotective effect of Stat1 deletion in murine aristolochic acid nephropathy
Wenguang Feng1, Wei-Zhong Ying1, Xingsheng Li2
1Division of Nephrology, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama.
Abstract:
Injured tubule epithelium stimulates a profibrotic milieu that accelerates loss of function in chronic kidney disease (CKD). This study tested the role of signal transducer and activator of transcription 1 (STAT1) in the progressive loss of kidney function in aristolochic acid (AA) nephropathy, a model of CKD. Mean serum creatinine concentration increased in wild-type (WT) littermates treated with AA, whereas Stat1-/- mice were protected. Focal increases in the apical expression of kidney injury molecule (KIM)-1 were observed in the proximal tubules of WT mice with AA treatment but were absent in Stat1-/- mice in the treatment group as well as in both control groups. A composite injury score, an indicator of proximal tubule injury, was reduced in Stat1-/- mice treated with AA. Increased expression of integrin-β6 and phosphorylated Smad2/3 in proximal tubules as well as interstitial collagen and fibronectin were observed in WT mice following AA treatment but were all decreased in AA-treated Stat1-/- mice. The data indicated that STAT1 activation facilitated the development of progressive kidney injury and interstitial fibrosis in AA nephropathy.
Insights
Signal transducer and activator of transcription 1 (STAT1) exacerbates kidney injury and fibrosis in chronic kidney disease (CKD). STAT1 deficiency protected mice from aristolochic acid-induced kidney damage, indicating STAT1
Area of Science:
- Nephrology
- Molecular Biology
- Immunology
Background:
- Injured kidney tubule epithelium promotes fibrosis and accelerates kidney function loss in chronic kidney disease (CKD).
- The role of signal transducer and activator of transcription 1 (STAT1) in CKD progression remains incompletely understood.
Purpose of the Study:
- To investigate the role of STAT1 in the progressive loss of kidney function in aristolochic acid (AA) nephropathy, a model of CKD.
- To determine if STAT1 activation contributes to kidney injury and interstitial fibrosis.
Main Methods:
- Comparison of wild-type (WT) and STAT1-deficient (Stat1-/-) mice treated with aristolochic acid (AA).
- Assessment of serum creatinine levels, kidney injury molecule-1 (KIM-1) expression, and composite injury scores.
- Evaluation of integrin-β6, phosphorylated Smad2/3, interstitial collagen, and fibronectin expression in kidney tissues.
Main Results:
- WT mice treated with AA showed increased serum creatinine, whereas Stat1-/- mice were protected.
- AA treatment induced KIM-1 expression in WT mice, but this was absent in Stat1-/- mice.
- Stat1-/- mice exhibited reduced composite injury scores, integrin-β6, phosphorylated Smad2/3, collagen, and fibronectin compared to WT mice.
Conclusions:
- STAT1 activation plays a critical role in facilitating progressive kidney injury and interstitial fibrosis in AA-induced nephropathy.
- Targeting STAT1 may offer a therapeutic strategy for mitigating kidney damage in CKD.
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