Heme oxygenase-1 inhibits renal tubular macroautophagy in acute kidney injury.
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.
Bolisetty
Subhashini
S
Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
Traylor
Amie M
AM
Kim
Junghyun
J
Joseph
Reny
R
Ricart
Karina
K
Landar
Aimee
A
Agarwal
Anupam
A
D058186:Acute Kidney Injury / Q000139:chemically induced / Q000201:enzymology* / Q000473:pathology; D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects; D001343:Autophagy; D002945:Cisplatin / Q000009:adverse effects; D051547:Heme Oxygenase-1 / Q000378:metabolism*; D006801:Humans; D007687:Kidney Tubules, Proximal / Q000201:enzymology* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017382:Reactive Oxygen Species / Q000378:metabolism
D000970:Antineoplastic Agents; D017382:Reactive Oxygen Species; D051547:Heme Oxygenase-1; D002945:Cisplatin