Aristolochic Acid Induces Renal Fibrosis and Senescence in Mice

• Published in: International journal of molecular sciences 2021-11, Vol.22 (22), p.12432
• Main Authors: Urate, Shingo, Wakui, Hiromichi, Azushima, Kengo, Yamaji, Takahiro, Suzuki, Toru, Abe, Eriko, Tanaka, Shohei, Taguchi, Shinya, Tsukamoto, Shunichiro, Kinguchi, Sho, Uneda, Kazushi, Kanaoka, Tomohiko, Atobe, Yoshitoshi, Funakoshi, Kengo, Yamashita, Akio, Tamura, Kouichi
• Format: Article
• Language: English
• Subjects: Abnormalities; Age; Aging; Aging - drug effects; Aging - genetics; Animals; Aristolochic acid; Aristolochic Acids - pharmacology; Atrophy; beta-Galactosidase - genetics; beta-Galactosidase - metabolism; Collagen - agonists; Collagen - genetics; Collagen - metabolism; Creatinine; Cyclin-Dependent Kinase Inhibitor p16 - genetics; Cyclin-Dependent Kinase Inhibitor p16 - metabolism; Cyclin-dependent kinases; Disease Models, Animal; Fibrosis; Galactosidase; Gene expression; Gene Expression Regulation; Genetic engineering; Humans; Hypoxia; Kidney - drug effects; Kidney - metabolism; Kidney - pathology; Kidney diseases; Kidneys; Kinases; Klotho protein; Klotho Proteins - genetics; Klotho Proteins - metabolism; Male; Mice; Mice, Inbred C57BL; Microscopy; Mitochondria; Mitochondria - drug effects; Mitochondria - metabolism; Mitochondria - pathology; Nephritis, Interstitial - chemically induced; Nephritis, Interstitial - genetics; Nephritis, Interstitial - metabolism; Nephritis, Interstitial - pathology; Nephropathy; Organs; Oxidative stress; Phenotypes; Proteins; Reactive oxygen species; Reactive Oxygen Species - agonists; Reactive Oxygen Species - metabolism; Renal Insufficiency, Chronic - chemically induced; Renal Insufficiency, Chronic - genetics; Renal Insufficiency, Chronic - metabolism; Renal Insufficiency, Chronic - pathology; Senescence; Signal Transduction; Transforming Growth Factor beta - agonists; Transforming Growth Factor beta - genetics; Transforming Growth Factor beta - metabolism; β-Galactosidase
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms222212432

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.