Role of PI3K-Akt and MAPK Signaling in Uranyl Nitrate-Induced Nephrotoxicity
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Uranium is a heavy metal of considerable environmental and occupational concern. It is well-known that the kidney is the major target organ of uranium exposure. Elucidating the mechanistic basis of uranium interactions is essential for monitoring the health risk. In the present study, we investigated the cellular mechanisms involved in uranyl nitrate-induced nephrotoxicity. Male Swiss albino mice were administrated with a single intraperitoneal dose of 2 and 4 mg/kg of uranyl nitrate at different time points 1, 3, 5, 7, 14, and 28 days. Uranyl nitrate intoxication-induced apoptosis in the kidney tissue was observed by TUNEL assay. To assess the proliferation, immunohistochemistry was performed using Ki67 proliferative marker followed by western blotting to confirm the involvement of key signaling molecules. The number of TUNEL positive nuclei peaked at third day after uranyl nitrate insult. The increased expression of proliferation marker Ki67 suggests the enhanced DNA repair process prominently at seventh day. Uranyl nitrate administration also resulted in activation of extracellular signal-regulated kinases (ERK), Akt, and c-Jun N-terminal kinases (JNK) expression. All these changes were found to be time-dependent. The result of the current study suggests that uranyl nitrate induces acute renal injury by activation of apoptosis through JNK pathway, while the early activation of signaling molecules Akt and ERK promotes the tubular cell proliferation and cell survival.
KeywordsUranyl nitrate Nephrotoxicity MAPK signaling Proliferation Apoptosis
The BRNS [Project No. 2010/36/69-BRNS] supported this work financially. This work was also supported by Yenepoya University through a junior research fellowship.
Compliance with Ethical Standards
Conflict of Interest
The authors declare that they have no conflict of interest.
Experiments were conducted after obtaining approval by the Institutional animal ethics committee (No. 1/2014). The animal care and handling was according to the CPCSEA guidelines for animal experimentation. All applicable international, national, and/or institutional guidelines for the care and use of animals were followed.
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