Tohoku J. Exp. Med., 2018 September, 246(1)

Demonstration of Mitochondrial Damage and Mitophagy in Cisplatin-Mediated Nephrotoxicity

MIKI ICHINOMIYA,1 AKINORI SHIMADA,1 NAOKI OHTA,1 ERINA INOUCHI,1 KIKUMI OGIHARA,1 YUKO NAYA,1 MASAKI NAGANE,2 TAKEHITO MORITA3 and MASAHIKO SATOH4

1Laboratory of Pathology, School of Life and Environmental Science, Azabu University, Sagamihara, Kanagawa, Japan
2Laboratory of Biochemistry, School of Veterinary Medicine, Azabu University, Sagamihara, Kanagawa, Japan
3Department of Veterinary Pathology, Tottori University, Tottori, Tottori, Japan
4Laboratory of Pharmaceutical Health Sciences, School of Pharmacy, Aichi Gakuin University, Nagoya, Aichi, Japan

Cisplatin is a chemotherapeutic widely used in the treatment of various types of solid tumors. Acute kidney injury is the most critical dose-limiting factor in cancer patients treated with cisplatin; mitochondrial dysfunction and resultant cell damage by reactive oxygen species released from damaged mitochondria are suspected to be involved in the kidney injury. Pathological features of mitochondrial damage in relation to cisplatin-mediated nephrotoxicity, however, is not fully described. The purpose of this study was to demonstrate mitochondrial damage and clearance of damaged mitochondria by mitophagy in cisplatin-mediated nephrotoxicity. Three groups of rats received a single intraperitoneal injection of cisplatin at 20 mg/kg and were sacrificed at 24, 48 and 72 hours after the treatment. A time-dependent increase in the number of damaged renal tubules and the serum levels of blood urea nitrogen, creatinine, and mitochondrial aspartate transaminase was observed in rats after the treatment. We showed the increased numbers of swollen and fragmented mitochondria, observed by electron microscopy, and of cytochrome c oxidase IV- and 8-nitroguanosine-positive intracytoplasmic granules, detected by immunohistochemistry, in the degenerated renal tubules of the treated animals. Moreover, activated autophagy process was indicated in the degenerated renal epithelial cells, based on the findings of immunohistochemistry of microtubule-associated protein 1 light chain 3 (LC3), an autophagy marker, and lysosomal-associated membrane protein 1 (LAMP-1), a lysosome marker, and swollen and fragmented mitochondria in autophagosomes. These results suggest that mitochondrial damage and clearance of damaged mitochondria by mitophagy is involved in cisplatin-mediated nephrotoxicity.

Key words —— cisplatin; mitochondria; mitophagy; nephrotoxicity; rat

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Tohoku J. Exp. Med., 2018, 246, 1-8

Correspondince: Akinori Shimada, Laboratory of Pathology, School of Life and Environmental Science, Azabu University, 1-17-71 Fuchinobe, Chuo-ku, Sagamihara, Kanagawa 252-5201, Japan.

e-mail: a-shimada@azabu-u.ac.jp