The absence of interleukin-6 enhanced arsenite-induced renal injury by promoting autophagy of tubular epithelial cells with aberrant extracellular signal-regulated kinase activation.
Sodium arsenite (NaAs)-induced autophagic cell death (ACD) of a mouse renal tubular epithelial cell line (mProx24), which expresses enhanced levels of interleukin-6 (IL-6), was reduced by the suppression of autophagy by 3-methyladenine or Atg7 knockdown. The inhibition of the IL-6/signal transducer and activator of transcription 3 (STAT3) signal pathway by anti-IL-6 antibody or a Jak2 inhibitor (AG490) exaggerated ACD of mProx24 cells after NaAs challenge, attenuating STAT3 activation and reciprocally enhancing extracellular signal-regulated kinase (ERK) phosphorylation. In contrast, an ERK inhibitor, PD98059, reduced NaAs-induced ACD in mProx24 cells. Subcutaneous injection of NaAs (12.5 mg/kg) into BALB/c (wild-type) mice enhanced intrarenal expression of IL-6, mainly produced by tubular cells, and caused severe renal injury characterized by hemorrhages, acute tubular necrosis, cast formation, and brush border disappearance, with increases in serum urea nitrogen (blood urea nitrogen) and creatinine levels. In addition, IL-6-deficient (IL-6(-/-)) mice exhibited exaggerated histopathological changes with higher blood urea nitrogen and creatinine levels. Moreover, in IL-6(-/-) mice treated with NaAs, ACD in renal tubular cells was significantly augmented, along with diminished STAT3 activation and reciprocal enhancement of ERK signaling, compared with wild-type mice. Finally, the administration of exogenous IL-6 into wild-type mice significantly reduced NaAs-induced ACD along with diminished ERK activation and eventually alleviated acute renal dysfunction. Thus, IL-6/STAT3 signal pathway could inhibit ERK activation, a crucial step for ACD, eventually attenuating NaAs-induced renal dysfunction.
Kimura
Akihiko
A
Department of Forensic Medicine, Wakayama Medical University, Wakayama 641-8509, Japan.
Ishida
Yuko
Y
Wada
Takashi
T
Hisaoka
Tomoko
T
Morikawa
Yoshihiro
Y
Sugaya
Takeshi
T
Mukaida
Naofumi
N
Kondo
Toshikazu
T
D000818:Animals; D018053:Arsenites; D001343:Autophagy / Q000187:drug effects; D001806:Blood Urea Nitrogen; D016026:Bone Marrow Transplantation; D003404:Creatinine / Q000097:blood; D004789:Enzyme Activation / Q000187:drug effects; D004847:Epithelial Cells / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology* / Q000648:ultrastructure; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D007150:Immunohistochemistry; D015850:Interleukin-6 / Q000172:deficiency* / Q000276:immunology / Q000494:pharmacology; D007674:Kidney Diseases / Q000097:blood / Q000201:enzymology / Q000473:pathology* / Q000503:physiopathology; D007685:Kidney Tubules, Collecting / Q000201:enzymology / Q000473:pathology* / Q000503:physiopathology / Q000648:ultrastructure; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics / Q000378:metabolism; D009500:Neutralization Tests; D050796:STAT3 Transcription Factor / Q000378:metabolism; D017670:Sodium Compounds
D018053:Arsenites; D003404:Creatinine; D048049:Extracellular Signal-Regulated MAP Kinases; D015850:Interleukin-6; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D050796:STAT3 Transcription Factor; D017670:Sodium Compounds; C494087:Stat3 protein, mouse; C017947:sodium arsenite; C421109:multidrug resistance-associated protein 1