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Aristolochic Acid Induces Renal Fibrosis and Senescence in Mice
Shingo Urate1, Hiromichi Wakui1, Kengo Azushima1
1Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan.
Abstract:
The kidney is one of the most susceptible organs to age-related impairments. Generally, renal aging is accompanied by renal fibrosis, which is the final common pathway of chronic kidney diseases. Aristolochic acid (AA), a nephrotoxic agent, causes AA nephropathy (AAN), which is characterized by progressive renal fibrosis and functional decline. Although renal fibrosis is associated with renal aging, whether AA induces renal aging remains unclear. The aim of the present study is to investigate the potential use of AAN as a model of renal aging. Here, we examined senescence-related factors in AAN models by chronically administering AA to C57BL/6 mice. Compared with controls, the AA group demonstrated aging kidney phenotypes, such as renal atrophy, renal functional decline, and tubulointerstitial fibrosis. Additionally, AA promoted cellular senescence specifically in the kidneys, and increased renal p16 mRNA expression and senescence-associated β-galactosidase activity. Furthermore, AA-treated mice exhibited proximal tubular mitochondrial abnormalities, as well as reactive oxygen species accumulation. Klotho, an antiaging gene, was also significantly decreased in the kidneys of AA-treated mice. Collectively, the results of the present study indicate that AA alters senescence-related factors, and that renal fibrosis is closely related to renal aging.
Insights
Aristolochic acid (AA) induces kidney aging and fibrosis in mice, showing potential as a model for studying age-related kidney decline. This research highlights the link between renal fibrosis and aging.
Area of Science:
- Nephrology
- Gerontology
- Cellular Biology
Background:
- Kidney aging is linked to renal fibrosis, a common endpoint in chronic kidney diseases.
- Aristolochic acid (AA) causes nephropathy (AAN) with fibrosis and functional decline.
- The relationship between AA-induced fibrosis and kidney aging is not well understood.
Purpose of the Study:
- To investigate Aristolochic acid nephropathy (AAN) as a potential model for kidney aging.
- To examine senescence-related factors in the kidneys following chronic AA administration.
Main Methods:
- Administered Aristolochic acid (AA) to C57BL/6 mice to create an AA nephropathy (AAN) model.
- Assessed kidney phenotypes, including atrophy, functional decline, and tubulointerstitial fibrosis.
- Measured cellular senescence markers (p16 mRNA, β-galactosidase activity), mitochondrial function, reactive oxygen species (ROS), and Klotho gene expression.
Main Results:
- AA-treated mice exhibited kidney aging phenotypes: atrophy, functional decline, and fibrosis.
- AA significantly promoted kidney cellular senescence, increasing p16 mRNA and β-galactosidase activity.
- Mitochondrial dysfunction, ROS accumulation, and decreased Klotho expression were observed in AA-treated kidneys.
Conclusions:
- Aristolochic acid (AA) alters kidney senescence-related factors, suggesting it induces kidney aging.
- Renal fibrosis in AA nephropathy (AAN) is closely associated with kidney aging processes.
- AAN serves as a valuable model for studying age-related kidney diseases and fibrosis.
