Abstract
Peroxisome proliferator-activated receptor-alpha (PPAR-α) and its exogenous activators (fibrates) promote autophagy. However, whether the deleterious effects of PPAR-α deficiency on doxorubicin (DOX)-induced podocytopathy are associated with reduced autophagy remains to be clarified. We investigated the mechanisms of PPAR-α in DOX-induced podocytopathy and tubular injury in PPAR-α knockout (PAKO) mice and in a murine podocyte cell line. DOX-treated PAKO mice showed higher serum levels of triglycerides and non-esterified fatty acids and more severe podocytopathy than DOX-treated wild-type mice, as evidenced by higher urinary levels of proteins and podocalyxin at 3 days to 2 weeks and higher blood urea nitrogen and serum creatinine levels at 4 weeks. Additionally, there was an increased accumulation of p62, a negative autophagy marker, in the glomerular and tubular regions in DOX-treated PAKO mice at Day 9. Moreover, DOX-treated PAKO mice showed more severe glomerulosclerosis and tubular damage and lower podocalyxin expression in the kidneys than DOX-treated control mice at 4 weeks. Furthermore, DOX treatment increased p-p53, an apoptosis marker, and cleaved the caspase-3 levels and induced apoptosis, which was ameliorated by fenofibrate, a PPAR-α activator. Fenofibrate further enhanced AMPK activation and autophagy under fed and fasting conditions. Conclusively, PPAR-α deficiency enhances DOX-induced podocytopathy, glomerulosclerosis, and tubular injury, possibly by reducing autophagic activity in mouse kidneys.
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MDPI and ACS Style
Matsuta, K.; Kamiyama, K.; Imamoto, T.; Takeda, I.; Masunaga, S.; Kobayashi, M.; Takahashi, N.; Kasuno, K.; Hara, M.; Iwano, M.;
et al. PPAR-α Insufficiency Enhances Doxorubicin-Induced Nephropathy in PPAR-α Knockout Mice and a Murine Podocyte Cell Line. Cells 2024, 13, 1446.
https://doi.org/10.3390/cells13171446
AMA Style
Matsuta K, Kamiyama K, Imamoto T, Takeda I, Masunaga S, Kobayashi M, Takahashi N, Kasuno K, Hara M, Iwano M,
et al. PPAR-α Insufficiency Enhances Doxorubicin-Induced Nephropathy in PPAR-α Knockout Mice and a Murine Podocyte Cell Line. Cells. 2024; 13(17):1446.
https://doi.org/10.3390/cells13171446
Chicago/Turabian Style
Matsuta, Kohei, Kazuko Kamiyama, Toru Imamoto, Izumi Takeda, Shinya Masunaga, Mamiko Kobayashi, Naoki Takahashi, Kenji Kasuno, Masanori Hara, Masayuki Iwano,
and et al. 2024. "PPAR-α Insufficiency Enhances Doxorubicin-Induced Nephropathy in PPAR-α Knockout Mice and a Murine Podocyte Cell Line" Cells 13, no. 17: 1446.
https://doi.org/10.3390/cells13171446
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