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Pharmacological activation of NQO1 increases NAD? levels and attenuates cisplatin-mediated acute kidney injury in mice.

ABSTRACT:

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Cisplatin is a widely used chemotherapeutic agent for the treatment of various tumors. In addition to its antitumor activity, cisplatin affects normal cells and may induce adverse effects, such as ototoxicity, nephrotoxicity, and neuropathy. Various mechanisms, such as DNA adduct formation, mitochondrial dysfunction, oxidative stress, and inflammatory responses, are critically involved in cisplatin-induced adverse effects. As NAD(+) is a cofactor for various enzymes associated with cellular homeostasis, we studied the effects of increased NAD(+) levels by means of

Nad(p)h

quinone oxidoreductase 1 (NQO1) activation using a known pharmacological activator (?-lapachone) in wild-type and NQO1(-/-) mice on cisplatin-induced renal dysfunction in vivo. The intracellular NAD(+)/NADH ratio in renal tissues was significantly increased in wild-type mice co-treated with cisplatin and ?-lapachone compared with the ratio in mice treated with cisplatin alone. Inflammatory cytokines and biochemical markers for renal damage were significantly attenuated by ?-lapachone co-treatment compared with those in the cisplatin alone group. Notably, the protective effects of ?-lapachone in wild-type mice were completely abrogated in NQO1(-/-) mice. Moreover, ?-lapachone enhanced the tumoricidal action of cisplatin in a xenograft tumor model. Thus, intracellular regulation of NAD(+) levels through NQO1 activation might be a promising therapeutic target for the protection of cisplatin-induced acute kidney injury.

SUBMITTER: Oh GS

PROVIDER: S-EPMC3944666 | biostudies-literature | 2014 Mar

REPOSITORIES: biostudies-literature

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Pharmacological activation of NQO1 increases NAD⁺ levels and attenuates cisplatin-mediated acute kidney injury in mice.

Oh Gi-Su GS Kim Hyung-Jin HJ Choi Jae-Hyuck JH Shen Aihua A Choe Seong-Kyu SK Karna Anzani A Lee Seung Hoon SH Jo Hyang-Jeong HJ Yang Sei-Hoon SH Kwak Tae Hwan TH Lee Chul-Ho CH Park Raekil R So Hong-Seob HS

Kidney international 20130911 3

PMID: 24025646

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Project description:The histone methyltransferase SET and MYND domain protein 2 (SMYD2) has been implicated in tumorigenesis through methylating histone H3 at lysine36 (H3K36) and some non-histone substrates. Currently, the role of SMYD2 in acute kidney injury (AKI) remains unknown. Here, we investigated the effects of AZ505, a highly selective inhibitor of SMYD2, on the development of AKI and the mechanisms involved in a murine model of cisplatin-induced AKI. SMYD2 and trimethylated histone H3K36 (H3K36Me3) were highly expressed in the kidney following cisplatin treatment; administration of AZ505 remarkedly inhibited their expression, along with improving kidney function and ameliorating kidney damage. AZ505 also attenuated kidney tubular cell injury and apoptosis as evidenced by diminished the expression of neutrophil gelatinase associated lipocalin (NGAL) and kidney injury molecule (Kim-1), reduced the number of TUNEL positive cells, decreased the expression of cleaved caspase-3 and the BAX/BCL-2 ratio in injured kidneys. Moreover, AZ505 inhibited cisplatin-induced phosphorylation of p53, a key driver of kidney cell apoptosis and reduced expression of p21, a cell cycle inhibitor. Meanwhile, AZ505 promoted expression of proliferating cell nuclear antigen and cyclin D1, two markers of cell proliferation. Furthermore, AZ505 was effective in suppressing the phosphorylation of STAT3 and NF-κB, two transcriptional factors associated with kidney inflammation, attenuating the expression of monocyte chemoattractant protein-1 and intercellular cell adhesion molecule-1 and reducing infiltration of F4/80+ macrophages to the injured kidney. Finally, in cultured HK-2 cells, silencing of SMYD2 by specific siRNA inhibited cisplatin-induced apoptosis of kidney tubular epithelial cells. Collectively, these results suggests that SMYD2 is a key determinant of cisplatin nephrotoxicity and targeting SMYD2 protects against cisplatin-induced AKI by inhibiting apoptosis and inflammation and promoting cell proliferation.