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Heme oxygenase-1 inhibits renal tubular macroautophagy in acute kidney injury.

ABSTRACT: Autophagy is a tightly regulated, programmed mechanism to eliminate damaged organelles and proteins from a cell to maintain homeostasis. Cisplatin, a chemotherapeutic agent, accumulates in the proximal tubules of the kidney and causes dose-dependent nephrotoxicity, which may involve autophagy. In the kidney, cisplatin induces the protective antioxidant heme oxygenase-1 (HO-1). In this study, we examined the relationship between autophagy and HO-1 during cisplatin-mediated acute kidney injury (AKI). In wild-type primary proximal tubule cells (PTC), we observed a time-dependent increase in autophagy after cisplatin. In HO-1(-/-) PTC, however, we observed significantly higher levels of basal autophagy, impaired progression of autophagy, and increased apoptosis after cisplatin. Restoring HO-1 expression in these cells reversed the autophagic response and inhibited apoptosis after treatment with cisplatin. In vivo, although both wild-type and HO-1-deficient mice exhibited autophagosomes in the proximal tubules of the kidney in response to cisplatin, HO-1-deficient mice had significantly more autophagosomes, even in saline-treated animals. In addition, ecdysone-induced overexpression of HO-1 in cells led to a delay in autophagy progression, generated significantly lower levels of reactive oxygen species, and protected against cisplatin cytotoxicity. These findings demonstrate that HO-1 inhibits autophagy, suggesting that the heme oxygenase system may contain therapeutic targets for AKI.

SUBMITTER: Bolisetty S

PROVIDER: S-EPMC3013546 | biostudies-literature | 2010 Oct

REPOSITORIES: biostudies-literature

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Heme oxygenase-1 inhibits renal tubular macroautophagy in acute kidney injury.

Bolisetty Subhashini S Traylor Amie M AM Kim Junghyun J Joseph Reny R Ricart Karina K Landar Aimee A Agarwal Anupam A

Journal of the American Society of Nephrology : JASN 20100812 10

Autophagy is a tightly regulated, programmed mechanism to eliminate damaged organelles and proteins from a cell to maintain homeostasis. Cisplatin, a chemotherapeutic agent, accumulates in the proximal tubules of the kidney and causes dose-dependent nephrotoxicity, which may involve autophagy. In the kidney, cisplatin induces the protective antioxidant heme oxygenase-1 (HO-1). In this study, we examined the relationship between autophagy and HO-1 during cisplatin-mediated acute kidney injury (AK ...[more]

PMID: 20705711

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Project description:Endotoxin-induced acute kidney injury (AKI) is commonly observed in clinical practice. Renal tubular epithelial cell (RTEC) pyroptosis is one of the main factors leading to the development of endotoxin-induced AKI. Mitochondrial dysfunction can lead to pyroptosis. However, the biological pathways involved in the potential lipopolysaccharide (LPS)-induced pyroptosis of RTECs, notably those associated with mitochondrial dysfunction, are poorly understood. Previous studies have demonstrated that heme oxygenase (HO)-1 confers cell protection via the induction of PTEN-induced putative kinase 1 (PINK1) expression through PTEN to regulate mitochondrial fusion/fission during endotoxin-induced AKI in vivo. Therefore, the present study investigated the role of HO-1/PINK1 in maintaining mitochondrial function and inhibiting the pyroptosis of RTECs exposed to LPS. Primary cultures of RTECs were obtained from wild-type (WT) and PINK1-knockout (PINK1KO) rats. An in vitro model of endotoxin-associated RTEC injury was established following treatment of the cells with LPS. The WT RTECs were divided into the control, LPS, Znpp + LPS and Hemin + LPS groups, and the PINK1KO RTECs were divided into the control, LPS and Hemin + LPS groups. RTECs were exposed to LPS for 6 h to assess cell viability, inflammation, pyroptosis and mitochondrial function. In the LPS-treated RTECs, the mRNA and protein expression levels of HO-1 and PINK1 were upregulated. Cell viability, adenosine triphosphate (ATP) levels and the mitochondrial oxygen consumption rate were decreased, whereas the inflammatory response, pyroptosis and mitochondrial reactive oxygen species (ROS) levels were increased. The cell inflammatory response and the induction of pyroptosis were inhibited, whereas the levels of mitochondrial ROS were decreased. In addition, the cell viability and ATP levels were increased in the WT RTECs following the upregulation of HO-1 expression. These effects were reversed by the downregulation of HO-1 expression. However, no statistically significant differences were noted between the LPS and the Hemin + LPS groups in the PINK1KO RTECs. Collectively, the findings of the present study indicate that HO-1 inhibits inflammation and regulates mitochondrial function by inhibiting the pyroptosis of LPS-exposed RTECs via PINK1.

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Heme oxygenase-1 inhibits renal tubular macroautophagy in acute kidney injury.

Publications

Heme oxygenase-1 inhibits renal tubular macroautophagy in acute kidney injury.

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